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ResearchIn-Press PreviewTherapeutics Open Access | 10.1172/JCI154152

LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade

Amber Hickman,1 Joost Koetsier,1 Trevin Kurtanich,1 Michael C. Nielsen,1 Glenn Winn,1 Yunfei Wang,1 Salah-Eddine Bentebibel,1 Leilei Shi,1 Simone Punt,1 Leila Williams,1 Cara Haymaker,1 Charles B. Chesson,1 Faisal Fa'ak,1 Ana Dominguez,1 Richard Jones,2 Isere Kuiatse,2 Amy R. Caivano,3 Sayadeth Khounlo,3 Navin D. Warier,3 Upendra Marathi,4 Robert V. Market,3 Ronald J. Biediger,3 John W. Craft Jr,5 Patrick Hwu,1 Michael A. Davies,1 Darren G. Woodside,3 Peter Vanderslice,3 Adi Diab,1 Willem W. Overwijk,1 and Yared Hailemichael6

1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States of America

2Department of Lymphoma & Myeloma, The University of Texas MD Anderson Cancer Center, Houston, United States of America

3Molecular Cardiology Research Laboratories, Texas Heart Institute, Houston, United States of America

4LLC, 7Hills Pharma, Houston, United States of America

5Department of Biology and Chemistry, University of Houston, Houston, United States of America

6The University of Texas MD Anderson Cancer Center, Houston, United States of America

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Published May 12, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI154152.
Copyright © 2022, Hickman 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 May 12, 2022 - Version history
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Abstract

The inability of CD8+ T effectors (Teff) to reach tumor cells is an important mechanism of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that is expressed on T cells. Here we show that 7HP349, a small molecule activator of Lymphocyte function–associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin-cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improve antitumor response. 7HP349 monotherapy had modest effects on anti- programmed death 1 (PD-1)–resistant tumors, whereas combinatorial treatment with anti- T-lymphocyte-associated protein 4 (CTLA-4) therapy increased CD8+ Teff intratumoral sequestration and synergized in inducing cancer regression, in cooperation with neutrophils. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression may improve response likelihood to anti-CTLA-4 therapies. Our results provided a proof-of-principle demonstration that LFA-1 activation could convert a T cell-exclusionary TME to a T-cell enriched TME through mechanisms involving cooperation with innate immune cells.

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