Immune Classification for the PD-L1 Expression and Tumour-Infiltrating Lymphocytes in Colorectal Adenocarcinoma

Abstract

Background Colorectal adenocarcinoma is the third most common cancer worldwide and a leading cause of cancer-related death. The recent emergence of diverse immunotherapeutic agents has made it crucial to interpret a complex tumour microenvironment intermingled with tumour-infiltrating immune cells to predict the immunotherapeutic response rate. However, in colorectal adenocarcinoma, studies are lacking that provide detailed analyses of programmed death-ligand 1 (PD-L1) and tumour-infiltrating lymphocytes (TIL) to elucidate their prognostic values and to identify immunotherapy-targetable subgroups, preferably with multiple immune-related biomarkers. In the present study, we categorize colorectal adenocarcinomas into four types of tumour immune microenvironments according to PD-L1 expression and TIL, analyse their prognostic values, and propose an immunotherapy-targetable subgroup.Methods Formalin-fixed, paraffin-embedded tissue samples of surgically resected primary colorectal adenocarcinomas (n = 489) were obtained and arrayed on tissue microarray blocks. Immunohistochemical stains for PD-L1, programmed cell death protein 1 (PD-1), cluster of differentiation 8 (CD8), and microsatellite instability (MSI) were performed and evaluated.Results Tumour microenvironment immune type (TMIT) I (PD-L1-positive tumour cells and CD8-high TIL) and type II (PD-L1-negative tumour cells and CD8-low TIL) showed the best and worst prognoses, respectively. PD-L1 overexpression was significantly associated with MSI status. PD-L1 immunoreactivity was positively correlated with TIL having CD8 or PD-1 overexpression.Conclusions TMIT I subgroup showed stronger CD8/PD-L1/PD-1 signalling interaction compared to the other TMIT. Therefore, we propose that the TMIT I subgroup is a candidate TMIT to predict effective response rate for existing immune checkpoint inhibitors and determine targetable subgroups for emerging therapies.

A high density of PD-L1-expressing immune cells is significantly correlated with favorable disease free survival in nonmetastatic colorectal cancer

“…[6] To make matters more complex, mismatch repair (MMR) status may differentially impact PD-L1 expression related to survival. In this study, similar to the findings of Noh et al, [8] we found that a high density of PD-L1 expression correlated with hereditary non-polyposis colorectal cancer (HNPCC) patients and early tumor stage; however, the significance of PD-L1 expression in MMR-proficient and MMR-deficient patients is currently unclear. Droeser et al [13] have demonstrated that a high PD-L1 expression in MMR-proficient CRC is correlated with improved overall survival, while Dunne et al [17] have reported that PD-L1 expression is associated with a significantly better DFS in MMR-deficient patients.…”

“…[1][2][3] However, different subsets of TILs are associated with various specific functions, and a variety of these subsets can improve therapeutic outcomes for CRC patients. [4][5][6][7][8] In contrast, immune escape by cancer cells has been increasingly reported in recent years. Continuous exposure to tumor antigens results in the exhaustion of immune cells (ICs) and leads to poor clinical outcomes.…”

CD8+ Tumour-Infiltrating Lymphocytes and Tumour Microenvironment Immune Types as Biomarkers for Immunotherapy in Sinonasal Intestinal-Type Adenocarcinoma

“…This contrasts with known strong immunogenic tumours such as skin melanoma, renal cell and bladder cancer or head and neck and lung SCC, where TMIT I characterizes 40–50% of cases [ 21 ]. On the other hand, ITAC is comparable to adenocarcinomas of other organs such as lung, colon and stomach, with reports of 12–14%, 19% and 23% TMIT I, respectively [ 21 , 28 , 37 , 38 ].…”

The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

“…Colt et al have drawn a contrary conclusion that infiltration of CD8+ T cells into cancer islands was more significantly associated with the relapse-free survival than CD8+ T cell infiltration into either total tumor or stroma, while the result was not related to ICIs therapy [64]. In the stroma, CD8+TILs show a strong positive association with positive PD-L1 expression [65,66]. Low stromal CD8+ T cells infiltration was positively correlated to an increased incidence of angiolymphatic invasion [67].…”