Yin and Wang et al. demonstrated that nerve growth factor (NGF) expression was predictive of poor prognosis and response to immunotherapy in patients with melanoma. Mechanistically, autocrine NGF signaled via tropomyosin receptor kinase A (TrkA) on melanoma cells, IFNγ responses and leading to immune exclusion. Meanwhile, paracrine NGF engaged with TrkA on effector T cells and dampened T cell receptor signaling and effector function. NGF–TrkA blockade with larotrectinib synergized with checkpoint blockade in melanoma mouse models, leading to cures and durable protection against reoccurrence by inducing a robust increase in low-affinity memory T cells.
Contributed by Shishir Pant
ABSTRACT: Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon _ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.
Author Info: (1) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Department of Immunology, Duke University School of Medicine, Durham, NC, US
Author Info: (1) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. Department of Immunology, Duke University School of Medicine, Durham, NC, USA. (2) Department of Immunology, Duke University School of Medicine, Durham, NC, USA. (3) Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. (4) TCRCure Biopharma, Durham, NC, USA. (5) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (6) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (7) TCRCure Biopharma, Durham, NC, USA. (8) TCRCure Biopharma, Chongqing, China. (9) TCRCure Biopharma, Chongqing, China. (10) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (11) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (12) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (13) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (14) Hervor Therapeutics, Hangzhou, China. (15) Department of Immunology, Duke University School of Medicine, Durham, NC, USA. (16) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. (17) Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. (18) Department of Molecular Oncology and Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (19) Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China. (20) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. (21) Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. xiao.fan.wang@duke.edu. (22) Department of Immunology, Duke University School of Medicine, Durham, NC, USA. Li_QiJing@imcb.a-star.edu.sg. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. Li_QiJing@imcb.a-star.edu.sg. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. Li_QiJing@imcb.a-star.edu.sg.
