Differential expression of PD‑L1 and PD‑L2 is associated with the tumor microenvironment of TILs and M2 TAMs and tumor differentiation in non‑small cell lung cancer

Abstract

To improve the treatment strategy of immune-checkpoint inhibitors for non-small cell lung cancer (NSCLC), a comprehensive analysis of programmed death-ligand (PD-L)1 and PD-L2 expression is clinically important. The expression of PD-L1 and PD-L2 on both tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was investigated, with respect to tumor-infiltrating lymphocytes (TILs) and M2 tumor-associated macrophages (TAMs), which are key components of the tumor microenvironment, in 175 patients with resected NSCLC. The TIL and M2 TAM densities were associated with the expression of PD-L1 on the two TCs (both P<0.0001) and ICs (both P<0.0001). The TIL and M2 TAM densities were also associated with the expression of PD-L2 on both TCs (P= 0.0494 and P= 0.0452, respectively) and ICs (P=0.0048 and P=0.0125, respectively). However, there was no correlation between the percentage of PD-L1-positive TCs and the percentage of PD-L2-positive TCs (r=0.019; P=0.8049). Meanwhile, tumor differentiation was significantly associated with the PD-L1 expression on TCs and ICs (P= 0.0002 and P<0.0001, respectively). By contrast, tumor differentiation was inversely associated with the PD-L2 expression on both TCs and ICs (P=0.0260 and P=0.0326, respectively). In conclusion, the combined evaluation of PD-L1 and PD-L2 expression could be clinically important in the treatment strategy of immune-checkpoint inhibitors in patients with NSCLC. In particular, the evaluation of PD-L2 expression may be necessary for patients with PD-L1-negative NSCLC.

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients

“…Further, we also assessed exoPD-L2 levels in tissue PD-L1 positive and negative patients and interestingly found that exoPD-L2 was significantly higher in tissue-PD-L1-patients, supporting a recent parallel study by Sumitomo et al in which they evaluated the expression of PD-L1 and PD-L2 in NSCLC patients by immunohistochemistry (54). This group found that PD-L1 expression on tumor cells was directly correlated with tumor differentiation while PD-L2 expression was inversely associated, hence suggested that combined assessment of PD-L1 and PD-L2 expression may be considered clinically significant for ICIs-treatment regime in NSCLC patients (54). Thus, our results suggest that NSCLC patients with PD-L1 negative profiles may be evaluated for PD-L2 expression and postulates that PD-L2 may be used as a new target for this group of patients.…”

“…in which they evaluated the expression of PD-L1 and PD-L2 in NSCLC patients by immunohistochemistry ( 54 ). This group found that PD-L1 expression on tumor cells was directly correlated with tumor differentiation while PD-L2 expression was inversely associated, hence suggested that combined assessment of PD-L1 and PD-L2 expression may be considered clinically significant for ICIs-treatment regime in NSCLC patients ( 54 ). Thus, our results suggest that NSCLC patients with PD-L1 negative profiles may be evaluated for PD-L2 expression and postulates that PD-L2 may be used as a new target for this group of patients.…”

Anti-PD-1 Monoclonal Antibodies (mAbs) Are Superior to Anti-PD-L1 mAbs When Combined with Chemotherapy in First-Line Treatment for Metastatic Non-Small Cell Lung Cancer (mNSCLC): A Network Meta-Analysis

“…Secondly, PD-L1 and PD-L2 expression do not correlate with one another. Poorly-differentiated tumors have been suggested to express more PD-L1 than PD-L2, while well-differentiated tumors express more PD-L2 than PD-L1 [56]. This differential expression of PD-L1 would be expected to impact the efficacy of anti-PD-L1 mAbs but not the efficacy of anti-PD-1 mAbs.…”

Development of an Albumin-Masked mutPD-1Ig as a Tumor Lesion-Selective Immune Checkpoint Inhibitor

“…PD-L1 is mainly expressed on hematopoietic cells, while PD-L2 is more widely expressed . In addition, PD-L2 expression is also observed in several cancer types. , The expression of PD-L2 in cancers negatively correlates with tumor-infiltrating lymphocytes, prognosis, and survival rate. − Studies on pancreatic ductal adenocarcinomas have found that PD-L2 inhibits CD8 + T cells in tumor tissues and promotes the proliferation of regulatory T cells, thereby establishing an immunosuppressive microenvironment . Whether PD-L1 and PD-L2 play nonredundant roles in promoting cancer immune evasion is unclear.…”