Prognostic effect of different PD-L1 expression patterns in squamous cell carcinoma and adenocarcinoma of the cervix

TLDR

PD‑L1 expressed on immune and tumor cells binds PD‑1 on T lymphocytes to inhibit their function, and while the PD‑1/PD‑L1 axis is a key immunotherapeutic target, its clinical relevance in cervical cancer remains largely unknown. The authors examined PD‑L1 expression in paraffin‑embedded cervical cancer samples from two cohorts—primary tumors (156 squamous cell carcinoma, 49 adenocarcinoma) and paired primary/metastatic tumors (96 SCC, 31 adenocarcinoma)—using immunohistochemistry, and identified CD163/CD14‑positive, M2‑like tumor‑associated macrophages expressing PD‑L1. Squamous cell carcinomas showed higher PD‑L1 positivity and more PD‑L1‑positive M2‑like macrophages, and diffuse PD‑L1 expression correlated with poorer disease‑free and disease‑specific survival, while in adenocarcinomas PD‑L1‑positive macrophages predicted worse disease‑specific survival; PD‑L1 expression was similar in primary and metastatic tumors but immune cells were more abundant around metastases, underscoring PD‑L1’s role in cervical cancer immune escape and supporting therapeutic targeting of the PD‑1/PD‑L1 pathway.

Abstract

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P<0.001). PD-L1-positive tumor-associated macrophages were found to express CD163 and/or CD14 by triple fluorescent immunohistochemistry, demonstrating an M2-like phenotype. Interestingly, disease-free survival (P=0.022) and disease-specific survival (P=0.046) were significantly poorer in squamous cell carcinoma patients with diffuse PD-L1 expression as compared with patients with marginal PD-L1 expression (i.e., on the interface between tumor and stroma) in primary tumors. Disease-specific survival was significantly worse in adenocarcinoma patients with PD-L1-positive tumor-associated macrophages compared with adenocarcinoma patients without PD-L1-positive tumor-associated macrophages (P=0.014). No differences in PD-L1 expression between primary tumors and paired metastatic lymph nodes were detected. However, PD-L1-positive immune cells were found in greater abundance around the metastatic tumors as compared with the paired primary tumors (P=0.001 for squamous cell carcinoma and P=0.041 for adenocarcinoma). These findings point to a key role of PD-L1 in immune escape of cervical cancer, and provide a rationale for therapeutic targeting of the PD-1/PD-L1 pathway.