The tumor microenvironment of non–small cell lung cancer impairs immune cell function in people with HIV
Shruti S. Desai, Syim Salahuddin, Ramsey Yusuf, Kishu Ranjan, Jianlei Gu, Lais Osmani, Ya-Wei Lin, Sameet Mehta, Ronan Talmon, Insoo Kang, Yuval Kluger, Hongyu Zhao, Kurt Schalper, Brinda Emu
Shruti S. Desai, Syim Salahuddin, Ramsey Yusuf, Kishu Ranjan, Jianlei Gu, Lais Osmani, Ya-Wei Lin, Sameet Mehta, Ronan Talmon, Insoo Kang, Yuval Kluger, Hongyu Zhao, Kurt Schalper, Brinda Emu
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Research Article AIDS/HIV Immunology Oncology

The tumor microenvironment of non–small cell lung cancer impairs immune cell function in people with HIV

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 samples from PWH and from people without HIV (PWOH), we used imaging mass cytometry, a linear mixed-effects model, and an artificial intelligence–based (AI-based) PageRank mathematical algorithm based on spectral graph theory to demonstrate that HIV-associated tumors have differential distribution of tumor-infiltrating CD8+ and CD4+ T cells, enriched for the expression of programmed cell death 1 (PD-1) and lymphocyte-activating gene 3 (LAG3), 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 those from 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 with PWOH. Additionally, cells from PWH, compared with those from PWOH, exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines. In conclusion, our study demonstrates that the HIV-associated TME sustained a unique immune landscape, showing evidence of immune cells with enhanced immunoregulatory phenotypes and impaired antitumor responses, with implications for responses to immune checkpoint blocker therapies.

Authors

Shruti S. Desai, Syim Salahuddin, Ramsey Yusuf, Kishu Ranjan, Jianlei Gu, Lais Osmani, Ya-Wei Lin, Sameet Mehta, Ronan Talmon, Insoo Kang, Yuval Kluger, Hongyu Zhao, Kurt Schalper, Brinda Emu

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Figure 7

Tumor-killing assay with circulating cells from PWH and PWOH.

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Tumor-killing assay with circulating cells from PWH and PWOH. PBMCs from...
PBMCs from PWOH (blue; n = 5) and PWH (red; n = 5) were incubated with PC9 tumor cells, an HLA-A2+ EGFR-mutant NSCLC tumor cell line, that were either in their native state or stimulated for 24 hours with IFN-γ and TNF-α. The T/E T cell ratio was 1:0, 1:2, or 1:5. The y axis represents the proportion of CD8+ T cells that expressed the exhaustion markers LAG3, TIM3, PD-1, or CD39 on CD8+ T cells (A); the proportion of CD8+ T cells expressing the activation markers CD25 and CD69 on CD8+ T cells (B); the proportion of CD8+ T cells that produced IL-2 or IFN-γ cytokines (C); and the proportion of EPCAM+ tumor cells expressing annexin V, a marker of cell death (D), upon exposure to PBMCs from PWH or PWOH. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed unpaired Student’s t test with Holm-Bonferroni correction for multiple comparisons.