A distinct innate lymphoid cell population regulates tumor-associated T cells.
Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses 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.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Sarah Q
SQ
Crome
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Linh T
LT
Nguyen
Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, California, USA.|Gorgas Memorial Institute of Health Studies, Panama City, Panama.
Sandra
S
Lopez-Verges
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada.
S Y Cindy
SY
Yang
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Bernard
B
Martin
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jennifer Y
JY
Yam
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada.
Dylan J
DJ
Johnson
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jessica
J
Nie
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Michael
M
Pniak
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Pei Hua
PH
Yen
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Anca
A
Milea
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Ramlogan
R
Sowamber
Division of Gynecologic Oncology, University Health Network, Toronto, Ontario, Canada.
Sarah Rachel
SR
Katz
Division of Gynecologic Oncology, University Health Network, Toronto, Ontario, Canada.
Marcus Q
MQ
Bernardini
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Blaise A
BA
Clarke
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Patricia A
PA
Shaw
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Philipp A
PA
Lang
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Hal K
HK
Berman
Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada.
Trevor J
http://orcid.org/0000-0002-8073-5888
TJ
Pugh
Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, California, USA.
Lewis L
http://orcid.org/0000-0003-1308-3952
LL
Lanier
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada.
Pamela S
PS
Ohashi
D017252:CD3 Complex / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000276:immunology*; D007167:Immunotherapy; D007378:Interleukins / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*; D000097043:Interleukin-22
D017252:CD3 Complex; D019002:CD56 Antigen; D016207:Cytokines; D007378:Interleukins; D055627:Natural Cytotoxicity Triggering Receptor 1; D000097043:Interleukin-22; C112260:NCR1 protein, human