ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1553042
This article is part of the Research TopicThe Application of Immune Checkpoint Inhibitors Combined with Chemotherapy in Tumor ImmunotherapyView all 13 articles
B and T lymphocyte attenuator (BTLA) and PD-1 pathway dual blockade promotes antitumor immune responses by reversing CD8 + Tcell exhaustion in non-small cell lung cancer
Provisionally accepted- 1Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China
- 2Clinical Immunology Laboratory, the First Affiliated Hospital of Soochow University, Suzhou, China
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Background: Immunotherapies targeting the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) have shown great promise for a subset of patients with non-small cell lung cancer (NSCLC). However, safe and robust combination therapies are still needed to bring the benefit to broader patient populations. Methods: we performed in vivo treatment with PD-L1 antibody in Lewis lung carcinoma (LLC)-derived murine NSCLC model. Expression of B and T lymphocyte attenuator (BTLA) was detected during treatment. We evaluated the effects of the combination of anti-BTLA and anti-PD-L1 mAbs on tumor growth and overall survival of mice. In addition, distribution and function of immune cells were analyzed by flow cytometry. The role of BTLA in human and murine CD8+ T cells and its impact on reversing exhausted phenotype of PD-1+CD8+ T cell by PD-L1 blockade were analyzed. Furthermore, we investigated expression and distribution of BTLA on lymphocytes in tumor microenvironment of different specimens from NSCLC patients. Results: There was no significant difference overall survival between anti-PD-L1 therapy and IgG in LLC-bearing mice, and BTLA expression was increased on CD8+ T cells after PD-L1 antibody treatment. LLC-bearing mice treated with combination of anti-BTLA and anti-PD-L1 therapy had an improved overall survival than anti-BTLA or anti-PD-L1 alone. Compared to monotherapy with anti-BTLA or anti-PD-L1, mice treated with combination therapy demonstrated increased infiltration of CD8+ and CD4+ T cells, as well as increased expression of IFN-γ, TNF-α and Ki-67 in CD8+ T cells. In addition, CD8+ T cells co-expressing BTLA and PD-1 exhibited the most exhausted phenotype to resist PD-L1 blockade therapy. Furthermore, BTLA+CD8+ T cells were abnormally increased in different specimens from NSCLC patients, and CD8+ T cells expressing BTLA in NSCLC microenvironment were correlated with clinical response to anti-PD-1 therapy in NSCLC patients.Conclusion: Our results show that BTLA and PD-1 cooperatively inhibit the activity of CD8+ T cells and are associated with resistance to PD-1/PD-L1 pathway blockade in NSCLC patients. Anti-BTLA blockade enhances the antitumor efficacy of anti-PD-L1 therapy. Dual BTLA and PD-1/PD-L1 blockade should be further explored to elicit potent antitumor CD8+ T-cell responses in NSCLC patients.
Keywords: NSCLC, BTLA, PD-1/PD-L1, Immunotherapy, combination
Received: 29 Dec 2024; Accepted: 30 Apr 2025.
Copyright: © 2025 Zhang, Yang, Zeng, Qu, Shen, Mu, Lei, Su, Mao, Gao, Liu, Chen and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zeyi Liu, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China
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