Local immune response depends on p16INK4a status of primary tumor in vulvar squamous cell carcinoma

Abstract

BackgroundThe p16Ink4a is not a surrogate marker for high-risk human papilloma virus (HPV) genotypes but indicates better prognosis in vulvar squamous cell carcinoma patients. Our recent study confirmed substantial mismatch between p16Ink4a and high-risk HPV-status as well as revealed that p16Ink4a-overexpression itself is an independent prognostic factor for vulvar cancer.AimTo determine significance of the tumor infiltrating immune cells and p16Ink4a–status for better outcome of patients with vulvar cancer.MethodsIntraepithelial tumor infiltrating lymphocytes: CD8+, CD4+, FOXP3+, CD56+, tumor associated macrophages: CD68+, and GZB+ cells were calculated in 85 vulvar squamous cell carcinomas with previously defined p16Ink4a and high-risk HPV-status. Number of intraepithelial CD8+, CD4+, FOXP3+, CD56+, CD68+ and GZB+ cells were compared between tumors with different p16INK4a status and overlapping high-risk HPV-status separately. Survival analyses included the Kaplan–Meier method, log-rank test and Cox proportional hazards model.Resultsp16Ink4a-negative tumors were more infiltrated by intraepithelial CD8+, CD4+ and GZB+ cells than p16Ink4a-positive tumors (p=0.032, p=0.016 and p=0.007 respectively). High-risk HPV-status did not correlate with the infiltration of immune cells. Median follow up was 89.20 months (range 1.7-189.5). High CD4+ and CD56+ indices were correlated with prognosis in p16Ink4a–positive cases (p=0.039 and p=0.013 respectively). Low CD68+ infiltrates were correlated with prognosis in p16Ink4a-negative cases (p=0.018). Conclusion: p16Ink4a-status impacts local immune surveillance as represented by tumor infiltrating immune cells. Immunologic effects contributing to clinical outcome might depend on p16Ink4a-overexpression.

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

“…Recently we have reported that p16 INK4a -overexpression modulates immune cells infiltration regardless to (hr)HPV-DNA status [ 5 ]. Patients with p16 INK4a -negative tumors although more infiltrated with TILs (CD8+, CD4+, GZB+ cells) had worse outcome than cases with p16 INK4a -positive vSCCs [ 5 , 15 ].…”

“…Recently we have reported that p16 INK4a -overexpression modulates immune cells infiltration regardless to (hr)HPV-DNA status [ 5 ]. Patients with p16 INK4a -negative tumors although more infiltrated with TILs (CD8+, CD4+, GZB+ cells) had worse outcome than cases with p16 INK4a -positive vSCCs [ 5 , 15 ]. Here CC-PD-L1 expression was frequently observed on more infiltrated p16 INK4a -negative vSCCs suggesting that anti-immune programmed death-ligand 1 (PD-L1) pathway is at least partially responsible for worse outcome in these patients.…”

“…This could partially explain, observed in this study, correlation between CC-PD-L1-postivity and higher intraepithelial immune infiltration as represented by CD4+, CD8+, FOXP3+ T cells. Additionally, CC-PD-L1-positivity was more frequently observed among p16 Ink4a -negative tumors which were found to be more infiltrated by TILs and TAMs [ 5 ]. Lack of prognostic effect of interaction between PD-L1 on cancer cells and PD-1 on TILs can reflect state of equilibrium between host immune response and cancer tissue, thus not influencing patient's overall survival.…”

“…Recently, we have found that cancer immune surveillance as represented by tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs) depends on p16 INK4a expression regardless to high-risk HPV-DNA status [ 5 ] as various immune effectors contribute to improved clinical outcomes in patients with p16-positive and p16 INK4a -negative tumors.…”

PD-L1 expression in anogenital and oropharyngeal squamous cell carcinomas associated with different clinicopathological features, HPV status and prognosis: a meta-analysis

“…However, IFN-γ, produced by TILs, seems not to be the main reason for the difference of PD-L1 expression between HPV positive and negative anogenital cancer patients, because no signi cant difference was identi ed in numbers of CD8 + TILs distributing in HPV positive and negative anal and cervical cancer patients [38,39]. In vulvar SCC, there was fewer number of CD8 + TILs in p16 positive cases compared with p16 negative [40]. Therefore, genetic background (genomic aberrations and aberrant oncogenic signaling) may take the primary responsibility for PD-L1 overexpression in anogenital cancers [17,41].…”