Galectin-9 Mediated T-cell Exhaustion Promotes HPV Anal Squamous Cell Carcinoma in HIV Patients
Introduction. Anal squamous cell carcinoma (ASCC) is a rare form of gastrointestinal cancer most often caused by HPV infection and recently growing in incidence. 1,3 Similar to other squamous cell carcinomas caused by HPV, HPV 16 and 18 are indicated in over 90% of ASCC cases.1,3 Carcinogenesis involves intraepithelial dysplasia of the anal squamocolumnar junction, and factors like prolonged HPV infection due to impaired immune response affect the likelihood of ASCC development.2 Current treatment approaches are not standardized, with varying levels of success in treatment of dysplastic lesions and ASCC.2 The highest incidence of ASCC continues to be in HIV positive men who have sex with men (MSM) who are at a 78 times greater risk of HPV-induced ASCC compared to the general population.6,7 Despite the recuperation of CD4+ counts in HIV+ patients on antiretroviral therapy, HIV+ MSM continue to show poor prognosis in the setting of HPV caused ASCC compared to HIV- patients.6 Differences in the HIV+ tumor microenvironment warrants additional examination in the context of ASCC. Methods. Immune cell infiltration was examined in HIV+ and HIV- anal dysplasia before and after electrocautery ablation.8 Virus associated tumors (VASTs) derived from HPV infected individuals were examined for tumor infiltrating lymphocyte (TIL) expression of Galectin-9, PD-1, and TIGIT pathways and the resulting impact on immune cell function.9 The effects of Gal-9 on T-cell terminal differentiation and dysfunction were examined.9 Gal-9 expression in HIV+ lymphocytes and resultant function were further assessed.10 The role of chronic inflammation in HIV+ cell lines pre-and post-antiretroviral therapy was compared to HIV- cells.11 Finally, HPV-immortalized cells were exposed to chronic inflammation and tumorigenic potential was measured.12 Results. HIV+ anal dysplasia demonstrated elevated CD8+ T-cell infiltration throughout epithelia compared to HIV- samples.8 VAST TILs exhibited upregulated Gal-9 expression and dysfunctional degranulation.9 HIV+ lymphocytes showed Gal-9 upregulation with a dysfunctional phenotype and TNF- production.10 HIV+ cells post ART demonstrated sustained elevated cytokine production, and HPV cell lines exposed to chronic inflammation exhibited enhanced tumorigenicity.11,12 Conclusions. Gal-9 acts as a marker of immune cell dysfunction in HIV+ patients, causing downstream effects such as exhausted and unresponsive T-cells, dysregulated cytokine release, and terminal differentiation phenotypes. T-cell dysfunction disrupts HPV clearance in HIV+ anal dysplasia, leading to prolonged infection and potentially enhances carcinogenesis via dysregulated inflammatory response. Gal-9 may serve as an upstream target for HIV+ individuals with anal dysplasia and warrants further investigation in prevention of ASCC.
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