Translational lung cancer research · 2026
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.
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Zhang Yingying, Li Yang, Feng Can, Yang Yunxin, Liang Ning, Qiao Lili, Xie Jian, Zhang Yan, Hu Pingping, Deng Guodong, Zhang Jiandong
Аннотация
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 in vivo administration of using BTLA and PD-1 antibodies, and local irradiation was performed on the tumors. During the treatment, we evaluated the effect of RT combined with anti-BTLA and anti-PD-1 therapies on tumor growth in mice. After the treatment, the expression level of BTLA in the tumor microenvironment was analyzed via Western blotting, the proportion of immune cells in tumor microenvironment and spleen was analyzed by flow cytometry, and related cytokine release was detected via enzyme-linked immunosorbent assay.
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+ and CD8+ T cells in the tumor microenvironment. Further mechanistic studies demonstrated that depletion of memory B cells reversed these antitumor effects, suggesting that anti-BTLA augments the efficacy of RT-based immunotherapy partly through the regulation of memory B cells. In line with this, the triple-therapy regimen (RT + anti-PD-1 + anti-BTLA) further enhanced the expression of antitumor cytokines.
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.
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 in vivo administration of using BTLA and PD-1 antibodies, and local irradiation was performed on the tumors. During the treatment, we evaluated the effect of RT combined with anti-BTLA and anti-PD-1 therapies on tumor growth in mice. After the treatment, the expression level of BTLA in the tumor microenvironment was analyzed via Western blotting, the proportion of immune cells in tumor microenvironment and spleen was analyzed by flow cytometry, and related cytokine release was detected via enzyme-linked immunosorbent assay.
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+ and CD8+ T cells in the tumor microenvironment. Further mechanistic studies demonstrated that depletion of memory B cells reversed these antitumor effects, suggesting that anti-BTLA augments the efficacy of RT-based immunotherapy partly through the regulation of memory B cells. In line with this, the triple-therapy regimen (RT + anti-PD-1 + anti-BTLA) further enhanced the expression of antitumor cytokines.
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.