Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma

Abstract

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P < 0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P < 0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P = 0.041) was maintained only when the tumors had low-level PD-L1 expression (P = 0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P < 0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

“…PD-1/PD-L1 signaling axis has been demonstrated to play a role in regulating tumor microenvironment of prostate cancer and colorectal cancer [13,14]. Lee et al [15] showed that 5% colorectal carcinomas exhibited high PD-L1 expression and 19% had elevated numbers of PD-1-positive tumor infiltrating lymphocytes. Gevensleben et al [10] found that 52.2% of 209 primary prostate cancer samples expressed moderate to high PD-L1 levels and PD-L1 positivity was prognostic for biochemical recurrence.…”

Programmed cell death ligand‐1 protein expression and CD274/PD‐L1 gene amplification in colorectal cancer: Implications for prognosis

“…Previous studies revealed an association between unfavorable clinical outcomes and tumoral PD‐L1 expression in patients with CRC, whereas other studies found no such associations . Some researchers suggested that the prognostic implication of PD‐L1 expression might depend on the mismatch repair status, but the outcomes were inconsistent. Our own survival analysis showed that the expression of PD‐L1 was correlated with poorer clinical outcomes in patients with CRC.…”

“…The prognostic implication of PD‐L1 expression has also been widely researched; its positivity in gastric, esophageal, and pancreatic cancers; glioblastoma; and renal cell carcinoma is reportedly associated with poor clinical outcomes . However, there are conflicting reports regarding the prognostic role of PD‐L1 expression in melanomas, lung cancer, and colorectal cancer (CRC) . These discrepant results could be attributed, at least partially, to the IHC assays themselves, including the various antibodies and methodologies used in different studies, the absence of a standard cut‐off value denoting positivity, and tumor heterogeneity for PD‐L1 expression.…”

“…[2][3][4][5][6][7] However, there are conflicting reports regarding the prognostic role of PD-L1 expression in melanomas, lung cancer, and colorectal cancer (CRC). 3,[8][9][10][11][12] These discrepant results could be attributed, at least partially, to the IHC assays themselves, including the various antibodies and methodologies used in different studies, the absence of a standard cut-off value denoting positivity, and tumor heterogeneity for PD-L1 expression. Amplification of the CD274 gene on chromosome 9p24.1, which encodes PD-L1, has been detected in subgroups of patients with certain malignancies such as Hodgkin's lymphoma, gastric cancer, and triple-negative breast cancer, [13][14][15] suggesting that gene amplification might be another method of detecting PD-L1 upregulation.…”

Targeting the PD-1 Pathway in MSI-Stable Metastatic Colorectal Cancer

“…High tumor-infiltrating CD8+ T cell lymphocytes were associated with a favorable outcome in MSI-H CRC patients. Tumors with low levels of CD8+ T lymphocytes had poor prognosis, regardless of PD-L1 expression [19].…”