Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Nathan E. Reticker-Flynn; Weiruo Zhang; Julia A. Belk; Pamela A. Basto; Nichole K. Escalante; Genay O.W. Pilarowski; Alborz Bejnood; Maria M. Martins; Justin A. Kenkel; Ian L. Linde; Sreya Bagchi; Robert Yuan; Serena Chang; Matthew H. Spitzer; Yaron Carmi; Jiahan Cheng; Lorna L. Tolentino; Okmi Choi; Nancy Wu; Christina S. Kong; Andrew J. Gentles; John B. Sunwoo; Ansuman T. Satpathy; Sylvia K. Plevritis; Edgar G. Engleman

doi:10.1016/j.cell.2022.04.019

Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Nathan E. Reticker-Flynn^*, Weiruo Zhang, Julia A. Belk, Pamela A. Basto, Nichole K. Escalante, Genay O.W. Pilarowski, Alborz Bejnood, Maria M. Martins, Justin A. Kenkel, Ian L. Linde, Sreya Bagchi, Robert Yuan, Serena Chang, Matthew H. Spitzer, Yaron Carmi, Jiahan Cheng, Lorna L. Tolentino, Okmi Choi, Nancy Wu, Christina S. KongAndrew J. Gentles, John B. Sunwoo, Ansuman T. Satpathy, Sylvia K. Plevritis, Edgar G. Engleman^*

^*Corresponding author for this work

Pathology

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

167 Scopus citations

Abstract

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

Original language	English
Pages (from-to)	1924-1942.e23
Journal	Cell
Volume	185
Issue number	11
DOIs	https://doi.org/10.1016/j.cell.2022.04.019
State	Published - 26 May 2022

Funding

Funders	Funder number
METAvivor Foundation
National Institutes of Health	U54 CA209971, S10OD025212, UM1HG012076, F32 CA189408, F31 CA196029
National Cancer Institute	U01CA260852
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK116074
Parker Institute for Cancer Immunotherapy

Keywords

ISGs
MHC-I
NK cells
PD-L1
Tregs
interferon
lymph nodes
metastasis
regulatory T cells
tolerance

UN SDGs

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

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10.1016/j.cell.2022.04.019

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Reticker-Flynn, N. E., Zhang, W., Belk, J. A., Basto, P. A., Escalante, N. K., Pilarowski, G. O. W., Bejnood, A., Martins, M. M., Kenkel, J. A., Linde, I. L., Bagchi, S., Yuan, R., Chang, S., Spitzer, M. H., Carmi, Y., Cheng, J., Tolentino, L. L., Choi, O., Wu, N., ... Engleman, E. G. (2022). Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell, 185(11), 1924-1942.e23. https://doi.org/10.1016/j.cell.2022.04.019

@article{3d45501065ec40b3a35d806f56668c90,

title = "Lymph node colonization induces tumor-immune tolerance to promote distant metastasis",

abstract = "For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.",

keywords = "ISGs, MHC-I, NK cells, PD-L1, Tregs, interferon, lymph nodes, metastasis, regulatory T cells, tolerance",

author = "Reticker-Flynn, {Nathan E.} and Weiruo Zhang and Belk, {Julia A.} and Basto, {Pamela A.} and Escalante, {Nichole K.} and Pilarowski, {Genay O.W.} and Alborz Bejnood and Martins, {Maria M.} and Kenkel, {Justin A.} and Linde, {Ian L.} and Sreya Bagchi and Robert Yuan and Serena Chang and Spitzer, {Matthew H.} and Yaron Carmi and Jiahan Cheng and Tolentino, {Lorna L.} and Okmi Choi and Nancy Wu and Kong, {Christina S.} and Gentles, {Andrew J.} and Sunwoo, {John B.} and Satpathy, {Ansuman T.} and Plevritis, {Sylvia K.} and Engleman, {Edgar G.}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = may,

day = "26",

doi = "10.1016/j.cell.2022.04.019",

language = "אנגלית",

volume = "185",

pages = "1924--1942.e23",

journal = "Cell",

issn = "0092-8674",

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Reticker-Flynn, NE, Zhang, W, Belk, JA, Basto, PA, Escalante, NK, Pilarowski, GOW, Bejnood, A, Martins, MM, Kenkel, JA, Linde, IL, Bagchi, S, Yuan, R, Chang, S, Spitzer, MH, Carmi, Y, Cheng, J, Tolentino, LL, Choi, O, Wu, N, Kong, CS, Gentles, AJ, Sunwoo, JB, Satpathy, AT, Plevritis, SK & Engleman, EG 2022, 'Lymph node colonization induces tumor-immune tolerance to promote distant metastasis', Cell, vol. 185, no. 11, pp. 1924-1942.e23. https://doi.org/10.1016/j.cell.2022.04.019

TY - JOUR

T1 - Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

AU - Reticker-Flynn, Nathan E.

AU - Zhang, Weiruo

AU - Belk, Julia A.

AU - Basto, Pamela A.

AU - Escalante, Nichole K.

AU - Pilarowski, Genay O.W.

AU - Bejnood, Alborz

AU - Martins, Maria M.

AU - Kenkel, Justin A.

AU - Linde, Ian L.

AU - Bagchi, Sreya

AU - Yuan, Robert

AU - Chang, Serena

AU - Spitzer, Matthew H.

AU - Carmi, Yaron

AU - Cheng, Jiahan

AU - Tolentino, Lorna L.

AU - Choi, Okmi

AU - Wu, Nancy

AU - Kong, Christina S.

AU - Gentles, Andrew J.

AU - Sunwoo, John B.

AU - Satpathy, Ansuman T.

AU - Plevritis, Sylvia K.

AU - Engleman, Edgar G.

PY - 2022/5/26

Y1 - 2022/5/26

N2 - For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

AB - For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

KW - ISGs

KW - MHC-I

KW - NK cells

KW - PD-L1

KW - Tregs

KW - interferon

KW - lymph nodes

KW - metastasis

KW - regulatory T cells

KW - tolerance

UR - http://www.scopus.com/inward/record.url?scp=85130534404&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.04.019

DO - 10.1016/j.cell.2022.04.019

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35525247

AN - SCOPUS:85130534404

SN - 0092-8674

VL - 185

SP - 1924-1942.e23

JO - Cell

JF - Cell

IS - 11

ER -

Lymph node colonization induces tumor-immune tolerance to promote distant metastasis

Abstract

Funding

Keywords

UN SDGs

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