Abstract 6762: Tumor immune microenvironment &genomic features of non-small cell lung carcinomas in patients with HIV (PWH)
Authors: Desai Shruti , Ranjan Kishu , Salahuddin Syim , Yusuf Ramsey , Gu Jianlei , Tang Daiwei , Kong Yong , Rajendran Barani Kumar , Zhao Hongyu , Kluger Yuval , Goldberg Sarah , Emu Brinda , Schalper Kurt Alex 
Published: April 2023

Abstract
Introduction: Lung cancer is the leading cause of cancer-related death among PWH with a relative risk that is over 3-fold higher compared to the uninfected population. In addition, HIV-infected patients with non-small cell lung cancer (NSCLC) have a significantly worse prognosis. The determinants for these associations remain uncertain.
Methods: We investigated the immune contexture of 18 primary NSCLCs from PWH and 19 clinicopathologically matched NSCLCs from HIV-negative cases represented in tissue microarrays using 37-plex Imaging Mass Cytometry (IMC) panels including cell phenotype markers (CK,CD4,CD8,CD20,CD45RO,CD25,etc), immunomodulatory targets (PD-L1,PD-L2,B7-H3,B7-H4,B2M,etc) and DNA damage response/repair (DDR) indicators (γH2AX, RAD51,BRCA1,53BP1,etc). The samples were analyzed using single-cell tissue segmentation and spatial analysis. A subset of cases was also studied using whole exome DNA sequencing (WES) and mRNA sequencing (RNAseq).
Results: NSCLCs from PWH showed comparable levels of tumor infiltrating lymphocytes (TILs) relative to HIV-negative cases with a trend towards a lower CD4+/CD8+ cell ratio. However, CD4+ and CD8+ TILs in PWH showed higher levels of markers associated with T-cell activation and dysfunction including GZB, CD25, Ki-67, PD-1, LAG-3, and TIM-3 than non-HIV tumors. The epithelial tumor cells in HIV-associated cases showed higher levels of the immunomodulatory ligands PD-L1, CD47, B7-H4 and VISTA; and altered levels of the DDR markers γH2AX, BRCA1 and 53BP1 relative to the non-HIV controls. Differences were also seen in tumor-associated macrophages consistent with an immune regulatory environment. The spatial analysis of tumor and immune cells revealed a distinct topographic distribution of these cells in HIV-associated malignancies. WES analysis showed a higher nonsynonymous tumor mutational burden in HIV-associated tumors (400 vs 202 mean mutations/exome) with increased predicted HLA class-I neoantigens and a numerically higher immunoediting score than the non-HIV group. Exploratory analysis identified enrichment in RYR2 and KIAA1671 gene mutations in HIV-associated malignancies. RNAseq revealed distinct mRNA expression profiles of HIV-positive and negative NSCLCs with a fraction of transcripts showing differential expression associated with tumor suppressor functions, interleukin signaling and DDR.
Conclusion: NSCLCs in PWH display profound immunological and genomic alterations suggesting defective immunosurveillance. Our study reveals novel characteristics of HIV-associated NSCLC with possible clinical implications for this growing and understudied population.
Citation Format: Shruti Desai, Kishu Ranjan, Syim Salahuddin, Ramsey Yusuf, Jianlei Gu, Daiwei Tang, Yong Kong, Barani Kumar Rajendran, Hongyu Zhao, Yuval Kluger, Sarah Goldberg, Brinda Emu, Kurt Alex Schalper. Tumor immune microenvironment &genomic features of non-small cell lung carcinomas in patients with HIV (PWH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6762.