Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma

Abstract

PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p<0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (p<0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (p=0.82). Heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, since PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false negative results, these areas should be specifically selected for assessment.

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

“…7,[28][29][30] However, PD-L1 expression might differ between primary tumor and metastases as described for renal cell carcinoma and lung adenocarcinoma. [31][32][33] Therefore, it must be pointed out that a majority (57%) of tumor samples in our study was from metastatic sites, while previous studies in PC determined PD-L1 expression in the pancreatic primary. 7,[27][28][29][30] In lymphoma patients, levels of sPD-L1 have been reported to be independent of tumoral PD-L1 expression.…”

Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma

“…In addition to measuring the abundance of CD8 + T cells at the invasive tumor margin (as described above), previous studies have attempted to predict clinical responses by assaying for PD-L1 expression on tumor cells using traditional immunohistochemical approaches (7)(8)(9)(10)17). These attempts have yielded variable results.…”

PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma

“…A similar spatial and temporal heterogeneity has been described in other malignancies such as clear cell renal carcinoma, melanoma, and lung cancer. [38][39][40][41] This finding has implications for designing clinical trials and for retesting of metastatic neoplasms, which may be more or less accessible than their primary counterparts. This is particularly relevant for cSCC as the histologic material of the primary site may not be easily available for testing in many metastatic cases.…”