Potential therapeutic target for PD1/PDL1 blockade in microsatellite medullary carcinomas based on PDL1 expression by tumor cells and infiltration by numerous PD1+ T lymphocytes.

Abstract

e14599 Background: PD1/PDL1 blockade showed therapeutic efficacy in only microsatellite (MSI) colorectal carcinomas (CRC), however, the profile of PDL1 and PD1 expression in CRC is only partially described. Methods: We thus analyzed on FFPE whole-tissue sections of 80 CRC, the expression profile of PDL1 by tumor and/or immune cells by immunohistochemistry (clone E1L3N) depending on the MSI status and the histological subtype, and correlated to the density of PD1+ and Tbet+ (able to secrete IFNg known to induce PDL1) tumor-infiltrating lymphocytes (TIL). Results: 78% of MSI CRC (32/41) overexpressed PDL1 either by tumor or immune cells versus 46% of MSS CRC (18/39) (p 0.005). This overexpression was heterogeneous within the same tumor in most of cases. Among MSI CRC, PDL1 was preferentially overexpressed in medullary carcinomas (MC, 19/21, 90%) compared with 65% (13/20) in non medullary adenocarcinomas (p 0.06). PDL1 expression by tumor cells was only observed in MSI CRC (19/41, 46% with PDL1 expression in more than 5% of tumor cells – score 1), and preferentially in MC (57% vs 5% in no medullary adenocarcinomas, with PDL1 expression in more than 50% of tumor cells – score 3, p 0.0005). Conversely, PDL1 expression by immune cells was observed in MSI CRC (23/41, 56% with PDL1 expression by more than 5 sheets of 50 positive cells) but also in MSS CRC (18/39, 43%) (p 0.5). The density of PD1+ cells was significantly correlated to the PDL1 expression, as well as the density of Tbet+ TIL. Conclusions: PDL1 expression is 1) heterogeneous in CRC, among CRC but also within the same tumor, 2) preferentially observed in MSI CRC (78%), especially in MC (90%), where PDL1 is expressed by tumor cells, 3) correlated with the density of PD1+ or Tbet+ TIL, and 4) observed in a significant proportion of MSS CRC (46%) by immune cells only. From a clinical point of view, PDL1 expression has to be determined at best in full tissue section and besides its preferential expression in MSI CRC, its significant frequency and expression profil (only by immune cells) in MSS CRC should be taken into account in the future clinical trials testing the efficacy of anti-PD1/PDL1 antibodies.