p.P476S mutation of RBPJL inhibits the efficacy of anti-PD-1 therapy in oesophageal squamous cell carcinoma by blunting T-cell responses.
Clin Transl Immunology
; 9(9): e1172, 2020.
Article
in En
| MEDLINE
| ID: mdl-32994998
ABSTRACT
OBJECTIVES:
Anti-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).METHODS:
We 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.RESULTS:
The 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)).CONCLUSIONS:
We 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Type of study:
Prognostic_studies
Language:
En
Journal:
Clin Transl Immunology
Year:
2020
Document type:
Article