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

Abstract

Background: The programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) axis may represent a target for cervical cancer; however, it is poorly understood in human immunodeficiency virus (HIV)-infected patients. Methods: We evaluated HIV-positive ( n = 42) and HIV-negative ( n = 110) women with locally advanced cervical cancer regarding their PD-L1 expression, determined by combined positive score (CPS) ⩾ 1 and tumor proportion score (TPS) ⩾ 25%, and PD-L1 copy number alterations, assessed by fluorescence in situ hybridization. Results: Regardless of HIV status, 84.9% and 44.8% of cases were PD-L1-positive according to CPS ⩾ 1 and TPS ⩾ 25%. Per CPS ⩾ 1, PD-L1 positive rate was similar between HIV-positive and HIV-negative women, whereas a significant difference was seen per TPS ⩾ 25%. Tumor size and parametrial invasion were correlated with PD-L1 positivity in HIV-negative women, whereas anti-retroviral therapy (ART) was correlated with TPS < 25%. Low CD4-positive cell counts were associated with CPS < 1 in HIV-positive women. No significant difference was observed in PD-L1 copy number status between HIV-positive and HIV-negative women. PD-L1 amplification and polysomy were independently associated with TPS ⩾ 25%, whereas the presence of parametrial invasion was independently associated with CPS ⩾ 1. Cancer stage and PD-L1 amplification were identified as independent predictors of recurrence-free survival [hazard ratio (HR) = 2.40 (1.32–4.36) and HR = 5.33 (1.94–14.61)] and cancer-specific survival [HR = 13.62 (5.1–36.38) and HR = 3.53 (1.43–8.69)]. PD-L1 polysomy was an independent predictor of locoregional recurrence-free survival [HR = 3.27 (1.27–8.41)]. HIV status and PD-L1 expression (CPS ⩾ 1 or TPS ⩾ 25%) were not associated with poor patient outcomes. Conclusion: PD-L1 amplification and polysomy are the strongest drivers of PD-L1 expression in cervical cancer, and could represent prognostic biomarkers for anti-PD-1/PD-L1 therapy. Cervical cancer biology may be modulated by HIV infection, CD4-positive cells, and HIV treatments.

Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

“…39,40 A previous study of HIV-positive patients with cervical squamous cell carcinoma showed that PD-L1 þ tumor cells are more radiosensitive and that those patients show better response with RT. 35 High CD8:FOXP3 ratio combined with negative PD-L1 expression was an independent and significant favorable predictive factor for local control. It is reported that it might be a useful biomarker of radiosensitivity in patients with laryngeal SCC receiving definitive RT.…”

“…CD4 count correlated positively with PD-L1 CPS higher than 1% and negatively with TPS higher than 25% in HIV-positive patients with cervical squamous cell carcinoma. 35 Such discrepancies may be attributed to a relatively small number of cases tested and different methodology in evaluating PD-L1 and different tumor microenvironments of cervical and anal SCC. Besides, it has been postulated that a decrease in CD4 count may result in decreased PD-L1 expression on tumor cells and antigen-presenting cells, secondary to decreased interleukins (IL-2) and interferon-c in the microenvironment.…”

“…On the other hand, when CD4 count increases, the immune system is enhanced and produces more cytokines, increasing PD-1/PD-L1 expression on immune cells and tumor cells. 35 More studies are needed to better understand the relationship of CD4-positive cells and PD-L1 expression in HIV-positive patients and the effect of antiretroviral therapies. Furthermore, an immunosuppressive subset of CD4 T cells (Tregs), characterized by the expression of a master regulatory transcription factor, forkhead box P3 protein (FOXP3), correlates with poor prognosis and low survival rates in some cancers and is favorable in others.…”

Identification of a 12-LncRNA long Lymph Node Metastasis Prognostic Signature for Cervical Cancer

“…Copy number ampli cation or deletion often results in abnormal expression of oncogene and tumor suppressor genes, as well as tumor cells abnormalities, including cell adhesion and recognition [43]. Prior evidence has con rmed that an increase in the copy number of the PD-L1 gene was closely associated with the anti-PD-1 / PD-L1 treatment of locally advanced cervical cancer [44]. Therefore, we analyzed the copy number pro le of 138 samples from TCGA cohort and grouped samples according to risk score after the removal of germline CNV data.…”

PD‐L1, PARP1, and MMRs as potential therapeutic biomarkers for neuroendocrine cervical cancer

“…CPS is obtained by the total number of PD‐L1 positive cells, including tumor cells, lymphocytes, and macrophages, divided by the total number of living tumor cells ×100. 22 When CPS≥1, PD‐L1 expression was positive.…”