HIV infection induces CD44+PD-L1+ tumor initiating cells in AIDS associated non-AIDS defining cancers

Abstract

Abstract The antiretroviral therapy (ART) significantly increased the number of aging HIV patients and the non-AIDS defining cancers (NADC) have become the most frequent co-morbidity and causes of death among HIV patients. The role of HIV infection in cancer initiation and progression is unclear. Tumor initiating cells (TIC) are responsible for chemo-resistance, metastasis and mortality. Our previous work demonstrated that tumor-intrinsic PD-L1 correlate with proportion (%) of TIC and virulence. Supernatants from HIV infected peripheral blood lymphocyte (PBMC) cultures (HIV-sup) significantly increased % TIC (CD44+PD-L1+) in two human tumor cell lines-SCC4 (squamous carcinoma) and HeLa (cervical cancer). HIV single stranded RNA (ssRNA) binds TLR7/8, and leads to immune activation and inflammation. The Cancer Genome Atlas database analyses showed that squamous cancer and cervical adenocarcinoma patients with TLR7/8 amplification had significantly poor overall survival. TLR7 agonist R848 led to significant increase in % TIC, whereas treatment of the cancer cells with HIV-sup in presence of TLR7/8 inhibitor ODN2088 reversed this effect. Similarly, pharmacological inhibition (by ACHP) of TLR7/8 mediated NFkB signaling pathway decreased TIC % two-fold, confirming HIV mediated TLR7/8 signaling has pro-TIC effects. High levels of inflammatory cytokine IFNα correlates with HIV load and persistent infection. Treatment with IFNα led to a significant increase in TIC whereas blocking IFNα-induced JAK signaling by ruxolitinib, in presence of HIV-sup reduced TIC significantly. Thus, our novel data gives insight into HIV induced host-pathogen interactions that lead to TIC prevalence.