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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI188458

CD8+ T cells in the tumor microenvironment modulate response to endocrine therapy in breast cancer

Fabiana Napolitano,1 Yunguan Wang,2 Dhivya R. Sudhan,1 Paula I. Gonzalez-Ericsson,3 Luigi Formisano,4 Nisha Unni,5 Shahbano Shakeel,5 James Z. Zhu,6 Khushi Ahuja,7 Lei Guo,6 María Rosario Chica-Parrado,1 Yuki Matsunaga,1 Pamela Luna,1 Chang-Ching A. Lin,1 Yasuaki Uemoto,1 Kyung-Min Lee,1 Hongli Ma,8 Nathaniel J. Evans,8 Alberto Servetto,1 Saurabh Mendiratta,1 Spencer D. Barnes,7 Roberto Bianco,4 Yisheng V. Fang,9 Lin Xu,6 Jeon Lee,7 Tao Wang,6 Justin M. Balko,10 Gordon B. Mills,11 Marilyne Labrie,12 Ariella B. Hanker,1 and Carlos L. Arteaga1

1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States of America

2Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

3Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy

5Department of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, United States of America

6Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Publ, University of Texas Southwestern Medical Center, Dallas, United States of America

7Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, United States of America

8Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

9Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States of America

10Departments of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbildt University Medical Center, Nashville, United States of America

11Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, United States of America

12Department of Immunology and Cell Biology, Faculty of Medicine and Health S, University of Sherbrooke, Sherbrooke, Canada

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Published December 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188458.
Copyright © 2025, Napolitano et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 9, 2025 - Version history
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Abstract

The role of the tumor immune microenvironment (TIME) in modulating responses to antiestrogen therapy in hormone receptor-positive (HR+) breast cancers remains unclear. We analyzed pre- and on-treatment biopsies from patients with HR+ breast cancer treated with letrozole to induce estrogen deprivation (ED). Stromal tumor-infiltrating lymphocytes, assessed by H&E-staining, and immune-related gene sets, including IFNɣ signaling, measured by RNA sequencing, were increased in ED-resistant tumors. Cyclic immunofluorescence and spatial transcriptomics revealed an abundance of CD8+ T cells and enhanced antigen processing and immune gene signatures in ED-resistant tumors. In this group, the expression of CXCL9, CXCL10, and CXCL11 — chemokine genes involved in CD8+ T cell recruitment — and the CXCR3 receptor were upregulated both before and after letrozole. CXCL11 levels were higher in conditioned media from HR+ breast cancer cells co-cultured with CD8+ T cells. Both recombinant CXCL11 and co-culture with CD8+ T cells promoted MCF7 and T47D cell growth in estrogen-free conditions. Finally, deletion combined with silencing of the CXCL11 receptors CXCR3 and CXCR7 in MCF7 cells impaired proliferation in response to exogenous CXCL11 and to co-culture with CD8+ T cells in estrogen-free conditions. These findings suggest that CD8+ T cell-associated CXCL11 in the TIME modulates the response of HR+ breast cancer cells to estrogen suppression.

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