Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

Jeremy Goc; Mengze Lv; Nicholas J. Bessman; Anne-Laure Flamar; Sheena Sahota; Hiroaki Suzuki; Fei Teng; Gregory G. Putzel; Gerard Eberl; David R. Withers; Janelle C. Arthur; Manish A. Shah; Gregory F. Sonnenberg

doi:10.1016/j.cell.2021.07.029

Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

Jeremy Goc, Mengze Lv, Nicholas J. Bessman, Anne-Laure Flamar, Sheena Sahota, Hiroaki Suzuki, Fei Teng, Gregory G. Putzel, Gerard Eberl, David R. Withers, Janelle C. Arthur, Manish A. Shah, Gregory F. Sonnenberg^*

^*Corresponding author for this work

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

Abstract

Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.

Original language	English
Pages (from-to)	5015-5030.e16
Number of pages	32
Journal	Cell
Volume	184
Issue number	19
Early online date	17 Aug 2021
DOIs	https://doi.org/10.1016/j.cell.2021.07.029
Publication status	Published - 16 Sept 2021

Bibliographical note

Acknowledgments:
We thank the Epigenomics and the Microbiome Cores of Weill Cornell Medicine and all contributing members of the JRI IBD Live Cell Bank, which is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family, and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. We thank members of the Sonnenberg Laboratory for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the NIH (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, and R01AI162936), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, The Dalton Family Foundation, and Linda and Glenn Greenberg. J.G. is supported by fellowships from the Crohn’s and Colitis Foundation (519428) and the Philippe Foundation. N.J.B. is supported by a fellowship from the NIH (F32AI124517). G.F.S. is a CRI Lloyd J. Old STAR. J.C.A. is supported by NIH (K01DK103952 and R01DK124617).

Keywords

innate lymphoid cells
colorectal cancer
microbiota
checkpoint blockade immunotherapy
intestinal inflammation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.07.029

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@article{390ebbc42056422cb43074de382895e7,

title = "Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer",

abstract = "Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.",

keywords = "innate lymphoid cells, colorectal cancer, microbiota, checkpoint blockade immunotherapy, intestinal inflammation",

author = "Jeremy Goc and Mengze Lv and Bessman, {Nicholas J.} and Anne-Laure Flamar and Sheena Sahota and Hiroaki Suzuki and Fei Teng and Putzel, {Gregory G.} and Gerard Eberl and Withers, {David R.} and Arthur, {Janelle C.} and Shah, {Manish A.} and Sonnenberg, {Gregory F.}",

note = "Acknowledgments: We thank the Epigenomics and the Microbiome Cores of Weill Cornell Medicine and all contributing members of the JRI IBD Live Cell Bank, which is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family, and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. We thank members of the Sonnenberg Laboratory for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the NIH (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, and R01AI162936), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, The Dalton Family Foundation, and Linda and Glenn Greenberg. J.G. is supported by fellowships from the Crohn{\textquoteright}s and Colitis Foundation (519428) and the Philippe Foundation. N.J.B. is supported by a fellowship from the NIH (F32AI124517). G.F.S. is a CRI Lloyd J. Old STAR. J.C.A. is supported by NIH (K01DK103952 and R01DK124617).",

year = "2021",

month = sep,

day = "16",

doi = "10.1016/j.cell.2021.07.029",

language = "English",

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journal = "Cell",

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TY - JOUR

T1 - Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

AU - Goc, Jeremy

AU - Lv, Mengze

AU - Bessman, Nicholas J.

AU - Flamar, Anne-Laure

AU - Sahota, Sheena

AU - Suzuki, Hiroaki

AU - Teng, Fei

AU - Putzel, Gregory G.

AU - Eberl, Gerard

AU - Withers, David R.

AU - Arthur, Janelle C.

AU - Shah, Manish A.

AU - Sonnenberg, Gregory F.

N1 - Acknowledgments: We thank the Epigenomics and the Microbiome Cores of Weill Cornell Medicine and all contributing members of the JRI IBD Live Cell Bank, which is supported by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation, the Sanders Family, and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. We thank members of the Sonnenberg Laboratory for discussions and critical reading of the manuscript. Research in the Sonnenberg Laboratory is supported by the NIH (R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, and R01AI162936), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, a Wade F.B. Thompson/Cancer Research Institute (CRI) CLIP Investigator grant, the Meyer Cancer Center Collaborative Research Initiative, The Dalton Family Foundation, and Linda and Glenn Greenberg. J.G. is supported by fellowships from the Crohn’s and Colitis Foundation (519428) and the Philippe Foundation. N.J.B. is supported by a fellowship from the NIH (F32AI124517). G.F.S. is a CRI Lloyd J. Old STAR. J.C.A. is supported by NIH (K01DK103952 and R01DK124617).

PY - 2021/9/16

Y1 - 2021/9/16

N2 - Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.

AB - Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.

KW - innate lymphoid cells

KW - colorectal cancer

KW - microbiota

KW - checkpoint blockade immunotherapy

KW - intestinal inflammation

U2 - 10.1016/j.cell.2021.07.029

DO - 10.1016/j.cell.2021.07.029

M3 - Article

SN - 0092-8674

VL - 184

SP - 5015-5030.e16

JO - Cell

JF - Cell

IS - 19

ER -

Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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