Zhang, Wang, Xiao, Liu et al. focused on the role of perineural invasion in the TME of triple negative breast cancer (TNBC). Data from clinical cohorts and mouse models showed that sensory neurons (the major TNBC neuron type) dysregulated the TME by stimulating a dense ECM. Mechanistically, tumor-derived NGF activated sensory neurons in the TME, leading to CGRP release, subsequent activation of its receptor RAMP1 (expressed mostly on CAFs), collagen deposition, and immune exclusion. Targeting sensory neurons with the RAMP antagonist rimegepant remodeled the TME and synergized with anti-PD-1 in TNBC mouse models.
Contributed by Katherine Turner
ABSTRACT: Innervation is critical in tumor progression. However, the involvement of sensory neurons in the ecosystem of triple-negative breast cancer (TNBC) remains poorly elucidated. Here, we decipher that sensory neurons, the dominant neuron type in the TNBC ecosystem, drive the immune-excluded tumor microenvironment (TME) by stimulating a dense extracellular matrix. Mechanistically, a high concentration of nerve growth factor (NGF) in TME triggers sensory neurons to secrete the neuropeptide calcitonin gene-related peptide (CGRP), thereby activating cancer-associated fibroblasts (CAFs) to secrete collagen. Specifically, CGRP binds to its receptor RAMP1 (receptor activity modifying protein 1), which is expressed mainly on CAFs, and subsequently activates cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein 1 (CREB1) signaling to increase collagen deposition. Clinically, targeting sensory neurons remodels the disordered TME and synergizes with anti-programmed cell death protein 1 (PD-1) immunotherapy in TNBC. Collectively, our findings reveal a connection between sensory neurons and CAFs that obstructs antitumor immunity in TNBC. The CGRP antagonist rimegepant thus has clinical translational potential as an immuno-sensitizer to augment tumor immunotherapy.
Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shangha
Author Info: (1) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (2) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (3) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: yixiao11@fudan.edu.cn. (4) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (5) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (6) Institute of Pediatrics, National Children's Medical Center, Children's Hospital, and Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Fudan University, Shanghai 200032, China. (7) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (8) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (9) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (10) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. (11) Institute of Pediatrics, National Children's Medical Center, Children's Hospital, and Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Fudan University, Shanghai 200032, China. Electronic address: jinfei_ni@fudan.edu.cn. (12) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China. Electronic address: zhimingshao@fudan.edu.cn. (13) Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China; Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China. Electronic address: yizhoujiang@fudan.edu.cn.
