Gao, He, and Wang et al. show that Trilaciclib (CDK4/6 inhibitor) inhibits NSCLC progression in immunocompetent, but not immunodeficient, mice bearing s.c. LLC and CMT167 tumors. Trilaciclib induced tumor cell senescence and SASP in a cGAS-STING-dependent manner, promoted infiltration and activation of anti-tumor CD177+ neutrophils in the tumor, and activated CD8+ T cells with enhanced effector and cytotoxic function, partly via a cytokine-dependent priming. Trilaciclib enhanced the efficacy of immune checkpoint inhibitors and reduced tumor growth, without observable toxicity, in an LLC tumor model and patient derived organoids.
Contributed by Shishir Pant
ABSTRACT: Immunotherapy-based combination approaches have improved treatment efficacy in advanced non-small cell lung cancer (NSCLC), but progressive disease remains a challenge. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor approved for myelopreservation in extensive-stage small cell lung cancer (ES-SCLC). Our results demonstrate that trilaciclib has antitumor potential in NSCLC without significant toxicity. It reprograms the tumor immune microenvironment by primarily increasing antitumor neutrophils and CD8(+) T cells. Trilaciclib induces tumor cell senescence and the senescence-associated secretory phenotype in a cGAS-STING-dependent manner, which further facilitates the infiltration and activation of CD177(+) neutrophils with anti-tumor properties. These neutrophils enhance CD8(+) effector T cell activation and promote antitumor immunity. Additionally, activated CD8(+) T cells recruit and activate neutrophils, forming a positive feedback loop. Combining trilaciclib with anti-PD-1 antibodies presents a promising strategy for NSCLC treatment.
Author Info: (1) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; Department of Thoracic Oncology, Lung Cancer Diagnosis and Tr
Author Info: (1) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100053, China. (2) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (3) National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. (4) National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. (5) National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Endoscopy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. (6) National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. (7) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (8) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (9) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (10) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (11) Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. (12) National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China. (13) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (14) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (15) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: zhiyongliu@tjmuch.com. (16) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: chenpeng@tjmuch.com. (17) Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; National Clinical Research Center for Cancer, National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: guohua@tjmuch.com.
