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ResearchIn-Press PreviewAIDS/HIVImmunologyOncology Open Access | 10.1172/JCI177310

Tumor microenvironment of non-small cell lung cancer impairs immune cell function among people with HIV

Shruti S. Desai,1 Syim Salahuddin,2 Ramsey Yusuf,3 Kishu Ranjan,1 Jianlei Gu,4 Lais Osmani,5 Ya-Wei Eileen Lin,6 Sameet Mehta,7 Ronen Talmon,5 Insoo Kang,5 Yuval Kluger,1 Hongyu Zhao,4 Kurt A. Schalper,1 and Brinda Emu1

1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

Find articles by Desai, S. in: PubMed | Google Scholar

1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

Find articles by Kang, I. in: PubMed | Google Scholar

1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

Find articles by Zhao, H. in: PubMed | Google Scholar |

1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

Find articles by Schalper, K. in: PubMed | Google Scholar

1Department of Pathology, Yale University School of Medicine, New Haven, United States of America

2Section of Infectious Diseases, Yale University School of Medicine, New Haven, United States of America

3Department of Ophthalmology, Yale University School of Medicine, New Haven, United States of America

4Department of Biostatistics, Yale University School of Medicine, New Haven, United States of America

5Section of Rheumatology, Yale University School of Medicine, New Haven, United States of America

6Department of Electrical and Computer Engineering, Technion - Israel Institute of Technology, Haifa, Israel

7Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, United States of America

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Published June 3, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI177310.
Copyright © 2025, Desai 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 June 3, 2025 - Version history
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Abstract

Lung cancer is the leading cause of cancer mortality among people with HIV (PWH), with increased incidence and poor outcomes. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) limits tumor-specific immune responses. With a matched cohort of NSCLC from PWH and people without HIV (PWOH), we used imaging mass cytometry, linear mixed effects model and AI-based pageRank mathematical algorithm based on spectral graph theory to demonstrate that HIV-associated tumors demonstrate differential distribution of tumor infiltrating CD8+ and CD4+ T cells, enriched for the expression of PD-1 and Lag-3, as well as activation and proliferation markers. We also demonstrate higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1 and VISTA), among tumor-associated macrophages. Discrimination of cells between tumors from PWH versus PWOH was confirmed by spectral graph theory with 84.6% accuracy. Furthermore, we noted differences in spatial orientation of immune cells within the TME of PWH compared to PWOH. Additionally, cells from PWH, compared to PWOH, exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines. In conclusion, our study demonstrates that the HIV-associated tumor microenvironment sustains a unique immune landscape, with evidence of immune cells with enhanced immunoregulatory phenotypes and impaired anti-tumor responses, with implications for response to immune checkpoint blocker therapies.

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