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Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer
Yohei Masugi1,2, Reiko Nishihara1,2,3,4,5,6, Tsuyoshi Hamada1,2
1Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts.
Abstract:
Expression of the immune checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by IHC in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2-expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn-like lymphoid reaction (Ptrend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn-like lymphoid reaction, a multivariable OR in the highest (vs. lowest) quartile of the percentage of PDCD1LG2-expressing tumor cells was 0.38 (95% confidence interval, 0.22-0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival (Ptrend > 0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2-expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis. Cancer Immunol Res; 5(11); 1046-55. ©2017 AACR.
Insights
Tumor programmed cell death 1 ligand 2 (PD-L2) expression is inversely associated with Crohn-like lymphoid reactions in colorectal cancer. This suggests PD-L2-expressing tumor cells may inhibit tertiary lymphoid tissue development during colorectal carcinogenesis.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Immune checkpoint ligand CD274 (PD-L1) suppresses antitumor immunity.
- The role of PDCD1LG2 (PD-L2) in the tumor microenvironment is unclear.
- PD-L2 may influence lymphocytic reactions in colorectal cancer.
Purpose of the Study:
- To investigate the association between tumor PDCD1LG2 expression and lymphocytic reactions in colorectal cancer.
- To determine if PDCD1LG2 expression correlates with immune cell infiltration and tertiary lymphoid structures.
Main Methods:
- Immunohistochemistry (IHC) used to assess tumor PDCD1LG2 expression in 823 colorectal cancer cases.
- Multivariable ordinal logistic regression analyzed associations with Crohn-like lymphoid reaction, peritumoral/intratumoral lymphocytic reactions, and tumor-infiltrating lymphocytes.
- Adjusted for microsatellite instability, methylation, and key gene mutations (KRAS, BRAF, PIK3CA).
Main Results:
- Tumor PDCD1LG2 expression showed a significant inverse association with Crohn-like lymphoid reaction (Ptrend = 0.0003).
- Higher PDCD1LG2 expression correlated with reduced likelihood of strong Crohn-like lymphoid reactions.
- No significant association found between PDCD1LG2 expression and other lymphocytic reactions or patient survival.
Conclusions:
- Tumor PDCD1LG2 expression is inversely associated with Crohn-like lymphoid reaction in colorectal cancer.
- PDCD1LG2-expressing tumor cells may play a role in suppressing the development of tertiary lymphoid tissues.
- Further research is warranted to elucidate the precise mechanisms of PD-L2 in colorectal cancer immunity.