Emma Russell

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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