Clinical significance of programmed cell death‐ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability

Abstract

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front.

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

“…[44][45][46][47] Possible explanations for these conflicting results could be either technical issues (mainly Tissue Micro-Arrays vs whole tissue sections) and/or interpretation criteria (staining intensity, membranous vs cytoplasmic staining, tumor vs immune PDL1+ cells). Only the recent studies reported by Korehisa et al and Valentini et al 48,49 , based on whole tissue sections, are consistent with our results, showing that PDL1 expression should be evaluated on whole tissue sections to take into account its spatial heterogeneity. Furthermore, our results showing a significant association between PDL1 expression by immune cells, but not by e1562834-12 tumor cells, and the density of PD1+ TILs, suggest the importance of assessing the PDL1 expression pattern by immune cells, more frequent than the tumor cell pattern in CRC (except in medullary carcinomas), to better appreciate its biological impact on the antitumor immune response.…”

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

“…14 However, MSI tumors highly up-regulate expression of multiple immune checkpoints. 11,30 Consistently, our study demonstrated that MSI-H CRCs displayed PD-1/PD-L1 overexpression, which might help CRC cells to survive from naturally immune eradication. Moreover, we found that MSI-H patients with PD-1/PD-L1 upregulation developed poorer survival than those with PD-1/PD-L1 downregulation, which may potentially define subsets of CRC that might be more sensitive to checkpoint blockade.…”

Differences in gene expression profiling and biomarkers between histological colorectal carcinoma subsets from the serrated pathway

“…4 Moreover, it has been recently demonstrated that, on the basis of higher expression of programmed death-ligand 1 (PD-L1) and a higher level of BRAF mutation, hmMSI-H patients are candidates for immune checkpoint and tyrosine kinase inhibitors, respectively. 12,13 In contrast, the frequency of KRAS mutation in SAC is even higher than in CC, 14,15 and most SACs are microsatellite-stable, making them refractory to anti-epidermal growth factor receptor or anti-PD-L1 agents. Therefore, the aim of this study was, by using molecular profiling, to ascertain which molecular features are responsible for such differences between SAC and hmMSI-H, with a view to identifying useful diagnostic biomarkers and potential molecular targets.…”

“…In contrast, hmMSI‐H is characterised by the occurrence of a Crohn‐like reaction and peritumoral and intratumoral infiltrates . Moreover, it has been recently demonstrated that, on the basis of higher expression of programmed death‐ligand 1 (PD‐L1) and a higher level of BRAF mutation, hmMSI‐H patients are candidates for immune checkpoint and tyrosine kinase inhibitors, respectively . In contrast, the frequency of KRAS mutation in SAC is even higher than in CC, and most SACs are microsatellite‐stable, making them refractory to anti‐epidermal growth factor receptor or anti‐PD‐L1 agents.…”