Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

Abstract

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

Pre-diagnostic anthropometry, sex, and risk of colorectal cancer according to tumor immune cell composition

“…In this regard, previous studies, including on the present cohort, have demonstrated that obesity is associated with an increased risk of mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors in both sexes, 25,26 whereas another study found a link of obesity and risk of tumors displaying dMMR/MSI tumors only in women . 27 Although no association was found between obesity and MSI in a previous study on the present cohort, 26 immune infiltration and PD-L1 expression on immune cells have been found to be significantly higher in dMMR tumors, [9][10][11] which is in line with the expected. 28 Colorectal cancer is a heterogeneous disease, with multiple differences between proximal and distal tumors, including immune cell infiltration.…”

“…The immunohistochemical stainings and assessments of other immune cell subsets, PD-1, and PD-L1 have been described previously. [9][10][11] In brief, for analyses of CD20 + B cells, and CD8 + and FoxP3 + T cells, the total number of stained cells (in the central tumor, the invasive margin, and in the peritumoral stroma) was used in the analyses, whereas immune cell-specific PD-L1 expression was annotated as the estimated percentage of stained cells and categorized as 0-9%, 10-49%, and 50-100% stained immune cells, and PD-L1 expression on tumor cells was annotated as the estimated percentage of stained cells and categorized as <1%, 1-4%, 5-9%, 10-49%, and 50-100% stained tumor cells. The number of CD8 + T cells was calculated by automated image analysis using the colocalization algorithm within the Halo image analysis software (Indica Labs, Corrales, NM).…”

“…7 The associations between the density of different immune cell subsets and disease stage, grade, tumor location, and mutation status have been investigated in numerous studies, 6,8 also in the herein investigated cohort. [9][10][11] However, the relationship with obesity has been sparsely described.…”

MicroRNA‐93‐5p expression in tumor tissue and its tumor suppressor function via targeting programmed death ligand‐1 in colorectal cancer

“…Thus, as an immune checkpoint, PD‐L1 has gained increasing attention for its significant role in the development, progression, and migration of tumors (Naidoo et al, 2016). PD‐L1, also known as the cluster of differentiation 274 (CD274) and B7 homolog 1 (B7‐H1), has been demonstrated to be upregulated in multiple tumor tissues (Koukourakis et al, 2018; Wan et al, 2018), including CRC (Dunne et al, 2016; Berntsson et al, 2018). MicroRNAs (miRNAs) are a group of endogenous gene‐encoded noncoding single RNAs of ~22 nucleotides in length (Anfossi et al, 2018).…”

First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro

“…This approach aims at converting 'cold' tumors into 'hot' tumors, where activated immune cells are able to effectively eliminate cancer cells. [9][10][11][12][13] Although classic cytotoxic chemotherapy has been traditionally considered immunosuppressive, various clinical studies demonstrate that it often interacts positively with immunotherapy. Some groups have shown that anticancer agents such as oxaliplatin induce cell death accompanied by the release of crucial signals, rendering cancer cells 'visible' to the immune system.…”