Antitumor T cells are subject to multiple mechanisms of negative regulation1,2,3. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses4,5,6 led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56+CD3− population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production. Transcriptome analysis and phenotypic characterization determined that regulatory CD56+CD3− cells exhibit low cytotoxic activity, produce IL-22, and have an expression profile that overlaps with those of natural killer (NK) cells and other ILCs. NKp46 was highly expressed by these cells, and addition of anti-NKp46 antibodies to TIL cultures abrogated the ability of these regulatory ILCs to suppress T cell expansion. Notably, the presence of these regulatory ILCs in TIL cultures corresponded with a striking reduction in the time to disease recurrence. These studies demonstrate that a previously uncharacterized ILC population regulates the activity and expansion of tumor-associated T cells.
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We thank the donors for participating in this study and C. Tran and C. Garcia-Batres for helpful comments. We thank the Princess Margaret Genomics Centre (Toronto, Canada) for performing RNA sequencing. We thank M. Pintiles for her advice regarding statistical analysis of results. S.Q.C. is a Banting Fellow and was supported by a Knudson postdoctoral fellowship. S.L.-V. was supported by a Cancer Research Institute/Irvington Institute postdoctoral fellowship and is now part of Sistema Nacional de Investigación (SNI) de SENACYT, Panamá. T.J.P. is supported by the Princess Margaret Cancer Foundation, the Canada Foundation for Innovation, the Leaders Opportunity Fund (CFI 32383), and the Ontario Ministry of Research and Innovation, Ontario Research Fund Small Infrastructure Program. P.A.L. is supported by the Alexander von Humboldt Foundation (SKA2010) and the German Research Council (LA2558/3-1, LA2558/5-1, SFB974, RTG1949). L.L.L. is an American Cancer Society Professor funded by US National Institutes of Health grants AI066897 and AI068129 and the Parker Institute for Cancer Immunotherapy. P.S.O. holds a Canada Research Chair in Autoimmunity and Tumor Immunity. Canadian Institutes for Health Research grant CCM 104887 and CIHR Foundation award FDN143220 to P.S.O. supported this work.
The authors declare no competing financial interests.
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Crome, S., Nguyen, L., Lopez-Verges, S. et al. A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 23, 368–375 (2017) doi:10.1038/nm.4278
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