What Does PD-L2 Tell Us About Advanced Colorectal Cancer?

Results show the presence of PD-L2 in the tumor may be an independent predictor of survival outcomes for patients with advanced stage colon carcinoma.

Colorectal cancer (CRC) is most common among older people, although rising obesity rates have increased its prevalence among younger people. If caught early, when it is still at the localized stage, the 5-year survival rate is 90%. The trouble is, CRC presents differently in different patients, and having clues to how the disease will progress can make a difference.

The role of programmed cell death 1 ligand (PD-L1) in suppressing immune response is well known in many cancers. But what about PD-L2? Now, investigators from China Medical University Hospital in Taichung, Taiwan, have published results that show how the presence of PD-L2 in the tumor may be an independent predictor of survival outcomes for patients with advanced stage colon carcinoma.

Their findings were published in Scientific Reports, a publication of Nature Research.

The study involved 1264 patients diagnosed at different stages of CRC: 175 at stage I, 456 at stage II, 406 at stage III, and 227 at stage IV. These patients underwent surgery between 2006 and 2014; postoperative chemotherapy was recommended for high-risk stage II patients and lymph node metastasis stage III patients who were identified based on their surgical specimens.

Immunohistochemical staining was performed, and PD-L2 levels were graded based on a sliding scale. A total of 259 patients with stage III (174 patients) and IV (85 patients) CRC were included and the PD-L2 mRNA expression data were retrieved from the open access Human Pathology Atlas. Factors analyzed included gender, age (younger or older than 65 years, tumor and node stage, perineural invasion, tumor location, CD8+ tumor-infltrating lymphocyte intensity (TIL), CD45+ TIL density, PD1+ TIL density, tumor PD-L1 level, and tumor PD-L2 level. Five-year overall survival (OS) was estimated with the Kaplan-Meier method.

“We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8+ tumor-infiltrating lymphocytes,” the authors wrote.

Patients who had elevated tumor PD-L2 levels had better OS compared with those patients with low PD-L2 levels (57% vs 40%, P< 0.001); this was especially true in advanced stage colon carcinoma patients, the authors reported. Conversely, low tumor PD-L2 expression was associated with an increased 5-year OS risk among advanced stage colon carcinoma patients.

The authors note that the link between PD-L2 expression and survival outcomes has been noted in other cancers, including pancreatic and esophageal cancer, although some studies have connected PD-L2 expression with poor survival. The authors note topic is controversial because of inconsistencies and that more data are needed. The current study also found evidence that PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, which the authors say suggests “that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity.”

PD-L2 may also have predictive value for anti-PD1 immunotherapy, recent studies suggest. The authors note that while both PD-L1 and PD-L2 share the same receptor, other receptors for PD-L2 exist and thus the lesser known protein could play a different role in regulating T-cell responses. But more work is needed to clarity its role.

“Since the infammatory microenvironment in the gastrointestinal tract plays a role in CRC progression via host-immunity interactions, the upregulation of tumor PD-L2 may be due to adaptive immunity, suggesting that PD-L2 may have prognostic value and can be considered a therapeutic target for immunotherapy in colon carcinoma,” the authors write.


Huang KCY, Chiang SF, Chen TW, et al. Prognostic relevance of programmed cell death 1 ligand 2 (PDCD1LG2/PD-L2) in patients with advanced stage colon carcinoma treated with chemotherapy. Nat Res Sci Rep 2020; 10:22330 Published December 18, 2020. doi.org/10.1038/s41598-020-79419-3

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