TGF-βsignaling suppresses tumor surveillance by inducing the differentiation of conventional NK cells into ILC1s
Yulong Gao1,2, Fernando Souza-Fonseca Guimaraes1,3,4, Kyohei Nakamura1, Arabella Young1,2, Jai Rautela3, Shin Foong Ngiow1,2, Nicholas D. Huntington3,4, Mark J. Smyth1,2*
1Immunology in Cancer and Infection, QIMR Berghofer Medical Research Institute, Australia 2School of Medicine, University of Queensland, Australia 3 Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Australia 4 Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade NK cell control remains incompletely defined. In this study we describe the previously unrecognized TGF-β-dependent differentiation of conventional NK (cNK) cells (CD49a-CD49b+Eomes+) into transitional (tILC1) (CD49a+CD49b+Eomes+) and induced ILC1 (iILC1) (CD49a+CD49b-Eomes-) populations. Assessment of RNA sequencing profiles of these three populations from tumors revealed distinct transcriptional profiles. In a variety of transplanted and de novo carcinogen-induced tumors, we observed increased tumor weight was associated with reduced cNK cell percentage, and a simultaneous increase in the proportion of tILC1. Interestingly, closer examination of tILC1s and iILC1s revealed these cells exhibited up-regulated immune checkpoint molecule expression (LAG-3, TIGIT and CTLA-4, etc.) and a lower IFN-γ/TNF-α production ratio. In vivo cytokine neutralization experiments in various tumor models showed while IFN-γ was protective against tumor, TNF-α promoted tumor growth and metastases. Importantly, by utilizing multiple transgenic mouse models, we demonstrated that cNK cells are crucial effector cells in cancer, while the anti-tumor functions of tILC1s and iILC1s are impaired. Our findings highlight the unexpected plasticity of cNK cells under pathophysiological conditions and reveal a novel mechanism by which tumors escape innate immune responses.