Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis

• Published in: Journal for immunotherapy of cancer 2022-04, Vol.10 (4), p.e004564
• Main Authors: Chaudhary, Omkar, Trotta, Diane, Wang, Kaicheng, Wang, Xun, Chu, Xiuping, Bradley, Chip, Okulicz, Jason, Maves, Ryan C, Kronmann, Karl, Schofield, Christina M, Blaylock, Jason M, Deng, Yanhong, Schalper, Kurt A, Kaech, Susan M, Agan, Brian, Ganesan, Anuradha, Emu, Brinda
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antibodies; Biomarkers; Cancer; Case-Control Studies; CD8-Positive T-Lymphocytes; HIV; HIV Infections - complications; HIV-1 - metabolism; Human immunodeficiency virus; Human papillomavirus; Humans; Immunotherapy; Immunotherapy Biomarkers; Infections; Lung cancer; Lymphocytes; Lymphoma; Medical diagnosis; Neoplasms - diagnosis; Programmed Cell Death 1 Receptor - metabolism; Transcription factors; Translational Medical Research; Tumor Biomarkers; Tumor necrosis factor-TNF
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2022-004564

BackgroundPeople living with HIV (PLWH) have increased risk of developing cancers after controlling traditional risk factors and viral suppression. This study explores whether T cells can serve as a marker of risk for cancer among HIV-infected virally suppressed patients.MethodsA nested case control study design was pursued with 17 cancer cases and 73 controls (PLWH without cancer)ouidentified among the US Military HIV Natural History Study cohort, and were matched for CD4 + count, duration of HIV infection, and viral suppression. Cells were obtained from PLWH on an average of 12 months prior to clinical cancer diagnosis. Expression of inhibitory receptors (PD-1, CD160, CD244, Lag-3, and TIGIT), and transcription factors (T-bet, Eomesodermin, TCF-1, and (TOX) was measured on CD8 +T cells from that early time point.ResultsWe found that cases have increased expression of PD-1 +CD160+CD244+ (‘triple positive’) on total and effector CD8 + compared with controls (p=0.02). Furthermore, CD8 +T cells that were both PD-1 +CD160+CD244+ and T-betdimEomeshi were significantly elevated in cases at time point before cancer detection, compared with controls without cancer (p=0.008). This was driven by the finding that transcriptional factor profile of cells was altered in cancers compared with controls. Triple-positive cells were noted to retain the ability for cytotoxicity and cytokine secretion mediated by expression of CD160 and PD-1, respectively. However, triple-positive cells demonstrated high expression of TOX-1, a transcription factor associated with T cell exhaustion.ConclusionIn conclusion, we have found a subset of dysfunctional CD8 +T cells, PD-1 +CD160+CD244+T-betdimEomeshi, that is elevated 12 months before cancer diagnosis, suggesting that peripheral T cell alterations may serve as a biomarker of increased cancer risk among PLWH.