Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.
Contributed by Shishir Pant
ABSTRACT: Therapies for triple-negative breast cancer (TNBC) still need innovative approaches, while repolarizing tumor-associated macrophages (TAMs) may offer a breakthrough in the targeted therapy and immunotherapy of TNBC. In this study, our group found that the small-molecule tyrosine kinase inhibitor DCC-2036 could induce repolarization of TAMs from M2 to M1 type and enhance anti-tumor CD8+ T cell immunity in TNBC. Mechanistically, targeting inhibition of the non-receptor tyrosine kinase hematopoietic cell kinase (HCK) in TAMs regulated the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-glutamine synthetase (GS)-HIF1α signaling pathway, leading to a reprogramming of TAM metabolism from oxidative phosphorylation to glycolysis. This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in interleukin (IL)-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036 and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.
Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of
Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (2) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (3) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (4) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (5) Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (6) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (7) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (8) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (9) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (10) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (11) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (12) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (13) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (14) Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421002, China. (15) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (16) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: zuxuyu@usc.edu.cn. (17) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: shenyingying1113@usc.edu.cn.
