Impact of antiretroviral drugs on PD‑L1 expression and copy number gains with clinical outcomes in HIV‑positive and ‑negative locally advanced cervical cancers

Abstract

Cervical cancer has become a leading cause of death in both HIV-infected and uninfected women. Previous studies have revealed that antiretroviral therapy (ART) possesses anti-human papillomavirus (HPV) and antitumour properties, potentially serving as an anticancer agent and improving functional immunity in HIV-positive individuals. However, to the best of our knowledge, no studies have examined the association between ART and the clinical outcome of patients with pre-existing invasive cervical cancer. The current study analysed 48 HIV-positive and 123 HIV-negative patients with locally advanced stage IB2-IVA cervical cancer between December 2008 and December 2016. Tumours were categorized based on programmed cell death-ligand 1 (PD-L1) immunoreactivity and copy number alterations in the PD-L1 gene, as determined by fluorescence in situ hybridization. The results revealed that ART-treated patients exhibited a lower prevalence of PD-L1 immunopositivity, PD-L1 amplification and polysomy compared with patients that did not receive ART and those that were HIV-negative. Furthermore, ART-treated patients with PD-L1 immunonegativity exhibited an improved recurrence-free survival (RFS) compared with patients that did not receive ART and HIV-negative individuals with PD-L1 immunopositivity (P=0.041 vs. P=0.030). Additionally, ART-exposed patients with PD-L1 disomy demonstrated improved locoregional recurrence-free survival (LRR) when compared with HIV-negative patients with PD-L1 amplification and polysomy (P=0.039 vs. P=0.007), RFS (P<0.001 vs. P=0.006) and cancer-specific survival (CSS) (P=0.021 vs. P=0.025). ART-exposed patients with PD-L1 disomy also exhibited improved RFS (P<0.001) and CSS (P<0.001) compared with HIV-negative patients with PD-L1 amplification. Improved LRRs were demonstrated in ART-exposed patients with PD-L1 disomy (P=0.028) compared with non-HIV patients with polysomy. Following multivariate analysis, International Federation of Gynaecology and Obstetrics stage and PD-L1 amplification were determined to be predictors of poor a RFS [hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.37–4.30; P=0.002 vs. HR, 7.03; 95% CI, 2.79–17.74; P<0.001) and CSS (HR, 11.47; 95% CI, 4.70–27.99; P<0.001 vs. HR, 4.05; 95% CI, 1.64–9.98; P=0.002). However, only PD-L1 polysomy was determined to be a predictor of poor LRR (HR, 2.50; 95% CI, 1.11–5.63; P=0.027). HIV status was not associated with poor outcomes, as determined using Cox models. The results of the current study indicated that ART may be used for the treatment of cervical cancer in both HIV-infected and uninfected patients. However, additional research is required to further elucidate these results.

PD-L1 protein expression and copy number gains in HIV-positive locally advanced cervical cancer

“…Our previous study showed that tumors of HIV-infected cervical cancer patients who had undergone antiretroviral therapy (ART) had lower prevalence of PD-L1 immunopositivity, PD-L1 amplification, and polysomy compared with patients who did not receive ART and those that were HIV-negative. 14 Having additional expression data on PD-L1 and its encoding gene in HIV-positive patients would be useful for clinical management.…”

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study

“…Only two of 19 (10.5%) had a PD‐L1–positive tumor, and response did not correlate with tumor PD‐L1 expression. ART exposure has been associated with decreased PD‐L1 expression in cervical cancer 23,24 . However, other groups have found that colorectal cancer and lung cancer in PLWH have similar PD‐L1 expression and PD‐1 expression of tumor‐infiltrating lymphocytes 25,26 …”

“…One of those two subjects had two sure has been associated with decreased PD-L1 expression in cervical cancer. 23,24 However, other groups have found that colorectal cancer and lung cancer in PLWH have similar PD-L1 expression and PD-1 expression of tumor-infiltrating lymphocytes. 25,26 Another objective of this study was to evaluate the effect of nivolumab on CD4/C8 populations and HIV viral load.…”

Viral proteases as therapeutic targets

“…Nelfinavir also interferes with late steps of adenovirus and herpesvirus replication in vitro , but it does not affect adenoviral cysteine protease or herpes serine protease ( Georgi et al, 2020 ; Kalu et al, 2014 ). Similarly, lopinavir could act against papillomaviruses through its interactions with host targets ( Barillari et al, 2018 ; Batman et al, 2011 ; Loharamtaweethong et al, 2019 ; Zehbe et al, 2011 ).…”