Foci of Programmed Cell Death-Ligand 1 (PD-L1)-positive Tumor Areas With Tumor-infiltrating Leukocytes (TILs) Evocative of a PD-1/PD-L1-related Adaptive Immune Resistance are Frequent in Merkel Cell Carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis have revolutionized the treatment of patients with Merkel cell carcinoma (MCC). To date, no biomarker conditions access to these ICIs in MCC. We compared the tumor microenvironment of PD-L1+ and PD-L1− areas in a case series of MCC searching for foci evocative of PD-1/PD-L1 adaptive immune resistance. Among 58 tumors studied on digitalized serial tissue sections, 11 (19%) were concluded as “PD-L1+ tumors” [≥1% positive tumor cells (TCs) using PD-L1 immunohistochemistry in the whole tumor slide]. In addition, among the remaining 47 (81%) “PD-L1− tumors,” we nevertheless also identified “PD-L1+ FOV” (ie, “field of view” of about 3 mm² containing ≥1% positive TCs) in 22 (38%) additional tumors. Comparison between paired “PD-L1+ field of view (FOV)” and “PD-L1− FOV” within tumors, and between “PD-L1+ tumors” and “PD-L1− tumors”, revealed correlations between PD-L1 positivity and the abundance of tumor-infiltrating leukocytes, arguing for areas of PD-1/PD-L1-related adaptive immune resistance at least in some foci of “PD-L1+ tumors” and also in “PD-L1− tumors.” Tumor heterogeneity consists in a challenge searching for biomarkers able to predict the response/nonresponse to ICIs. Progress in digital pathology and multiplex immunolabeling may permit to overcome this challenge by better analyzing the interactions between TCs and immune and nonimmune non-TCs in the same tissue section. This approach of tumor heterogeneity may contribute to elucidate and to predict why some patients respond impressively to ICIs, whereas others do not.

The presence of Merkel cell carcinoma polyomavirus is associated with a distinct phenotype in neoplastic Merkel cell carcinoma cells and their tissue microenvironment

“…These results confirm previously published data [10][11][12][13][14][15] and extend these observations to the identification of specific T-cell, macrophage and B-cell subsets whose presence is associated with MCPyV. Our data concerning PDL1 expression are largely consistent with those recently published by Walsh and coworkers [11], i.e., PDL1 is mainly expressed by peritumoral macrophages rather than neoplastic cells [13,23]: in our series, PDL1 expression by neoplastic cells was observed in just 22/179 (12%) cases, a slightly lower proportion than that found by Wehkamp et al and Benigni et al [24,25]. Our results are basically consistent with those of Miller et al, who showed that MCPyV-positive tumors had a strikingly more clonal intratumoral TCR repertoire than MCPyV-negative tumors [26].…”

Association of Merkel Cell Polyomavirus Status With p53, RB1, and PD-L1 Expression and Patient Prognosis in Merkel Cell Carcinomas: Clinical, Morphologic, and Immunohistochemical Evaluation of 17 Cases

“…In a large series of studies by Butala et al, 24 TILs status was shown to increase overall survival in patients with non-metastatic MCC. Other studies have indicated that not only the presence of TILs but also their immunologic properties are important in prognoses 25–28 . However, in our study, no research was conducted on the immunohistochemical properties of TILs.…”

“…Other studies have indicated that not only the presence of TILs but also their immunologic properties are important in prognoses. [25][26][27][28] However, in our study, no research was conducted on the immunohistochemical properties of TILs.…”

Updates on the diagnosis, current and future therapeutic options in Merkel-cell carcinoma

“…This paradoxical correlation between the level of PDL-1 expression and improved outcomes has only been observed in MCC and some breast cancers [34]. Increased heterogeneity of tumor microenvironment may be another reason why some of the MCC tumors respond well to immune checkpoint inhibitors, while others may not [35]. Progress in digital pathology and multiplex immunolabeling may allow for more predictability of tissue response to immune checkpoint inhibitors prior to treatment [35].…”