P.P476S mutation of RBPJL inhibits the efficacy of anti‐PD‐1 therapy in oesophageal squamous cell carcinoma by blunting T‐cell responses

Abstract

ObjectivesAnti‐PD‐1 immune checkpoint blockade represents the onset of a new era in cancer immunotherapy. However, robust predictors are necessary for screening patients with immune checkpoint‐responsive oesophageal squamous cell carcinoma (ESCC).MethodsWe obtained biopsy samples from an ESCC patient with mixed responses. The expression of CD4, CD8, CD68, PD‐L1, RBPJL and IL‐16 was analysed by immunohistochemistry, and the correlation with prognostic value was obtained from the GEPIA portal. T‐cell functions were examined by flow cytometry, MTS and transwell assays. The secreted cytokines were identified using an Inflammation Array Kit. The concentration of soluble IFN‐γ was measured by enzyme‐linked immunosorbent assay. The clinical benefit of RBPJL was examined in a PBMC xenograft mouse model.ResultsThe patient had an exceptional clinical response with shrinkage of the primary oesophageal and lung metastatic lesions as well as enlargement of liver metastatic lesions after toripalimab monotherapy. Four liver‐specific gene mutations were identified. RBPJL showed better response to toripalimab in the PBMC cell‐derived xenograft (CDX) ESCC model. Conditional medium from RBPJL overexpression induced chemotaxis and proliferation of T lymphocytes, as well as Th2/Th1 differentiation through the RBPJL‐NF‐κB‐IL‐16 axis in vitro. These functions were all inhibited by the p.P476S mutation of RBPJL (RBPJL (p.P476S)).ConclusionsWe report for the first time that RBPJL (p.P476S) promotes tumor growth in ESCC and inhibits the efficacy of anti‐PD‐1 therapy through blunting T‐cell responses. Our findings provide a potential new predictor for evaluating the efficacy of anti‐PD‐1 therapy in ESCC patients.