BTLA and PD-1 combined with radiotherapy for enhancing antitumor immune response in lung cancer via the regulation of memory B cells to promote T-cell infiltration.

Background: Radiotherapy (RT) combined with immunotherapy targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) has become one of the most promising strategies for treating patients with non-small cell lung cancer (NSCLC). However, this combined approach remains to be optimized. This study systematically evaluated the antitumor efficacy and immune-cell infiltration characteristics of dual-immune checkpoint blockade combined with RT in order to develop an experimental basis for refining precise treatment schemes for patients with lung cancer. Methods: The expression and distribution of B- and T-lymphocyte attenuator (BTLA) on lymphocytes in the tumor microenvironment of patients with NSCLC were investigated through use of the Gene Expression Omnibus (GEO) database. A Lewis lung carcinoma (LLC) mouse model was created via the Results: Reanalysis of the GEO database revealed that elevated BTLA expression may contribute to immunotherapy resistance in certain patients. In the mouse lung cancer model, RT increased BTLA expression in tumor tissues. Compared with the RT combined with anti-BTLA or anti-PD-1 mono-immunotherapy, RT combined with dual immunotherapy of anti-PD-1 and anti-BTLA significantly inhibited tumor growth and increased the proportions of CD4 Conclusions: RT increased BTLA expression in the mouse tumor microenvironment. Anti-BTLA blockade enhanced the antitumor efficacy of RT combined with anti-PD-1 therapy by regulating the proportion of memory B cells in the mouse spleen and promoting T-cell infiltration into the tumor microenvironment. These findings provide a novel perspective for applying RT in combination with immunotherapy in patients with NSCLC.