Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

Can Cui; Jiawei Wang; Eric Fagerberg; Ping Min Chen; Kelli A. Connolly; Martina Damo; Julie F. Cheung; Tianyang Mao; Adnan S. Askari; Shuting Chen; Brittany Fitzgerald; Gena G. Foster; Stephanie C. Eisenbarth; Hongyu Zhao; Joseph Craft; Nikhil S. Joshi

doi:10.1016/j.cell.2021.11.007

Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

Can Cui, Jiawei Wang, Eric Fagerberg, Ping Min Chen, Kelli A. Connolly, Martina Damo, Julie F. Cheung, Tianyang Mao, Adnan S. Askari, Shuting Chen, Brittany Fitzgerald, Gena G. Foster, Stephanie C. Eisenbarth, Hongyu Zhao, Joseph Craft^*, Nikhil S. Joshi^*

^*Corresponding author for this work

Medicine, Allergy Division

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

214 Scopus citations

Abstract

CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.

Original language	English (US)
Pages (from-to)	6101-6118.e13
Journal	Cell
Volume	184
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2021.11.007
State	Published - Dec 9 2021

Funding

We thank the N.S.J. and J.C. laboratory members for reviewing the manuscript; Z. Chen, C. Yang, and N. Ruddle for helpful discussions; and W. Wei for important guidance on statistical analysis. We also thank the Yale Flow Cytometry Core, Yale Keck DNA Sequencing Facility, Yale School of Medicine Histology Facility, and NIH Tetramer Core Facility. SW HEL mice were kindly provided by Dr. Robert Brink. Figures 2 A, S4 B, S6 A, and S6B and the graphical abstract were created with https://www.biorender.com . This work was supported by grants from the NCI ( K22CA200912 and 1RO1CA237037-01A1 to N.S.J.), NIH ( R37AR40072 and AR074545 to J.C.), and Yale SPORE in Lung Cancer (1P50CA196530 1P50CA196530 to N.S.J. and J.C.) and a Pilot Grant from Yale Cancer Center (to N.S.J. and J.C.). C.C. was supported by the Gruber Science Fellowship and Richard K. Gershon Research Fellowship. J.F.C., K.A.C., and B.F. were supported by the Yale Immunobiology NIH T32 training grant ( 5T32AI007019 ).

Keywords

B cell
CD8 T cell
IL-21
T follicular helper cell
lung cancer
neoantigen

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.cell.2021.11.007

Cite this

Cui, C., Wang, J., Fagerberg, E., Chen, P. M., Connolly, K. A., Damo, M., Cheung, J. F., Mao, T., Askari, A. S., Chen, S., Fitzgerald, B., Foster, G. G., Eisenbarth, S. C., Zhao, H., Craft, J., & Joshi, N. S. (2021). Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell, 184(25), 6101-6118.e13. https://doi.org/10.1016/j.cell.2021.11.007

@article{2cc90aa883f94ce5b6e646b6859dd0ca,

title = "Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses",

abstract = "CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.",

keywords = "B cell, CD8 T cell, IL-21, T follicular helper cell, lung cancer, neoantigen",

author = "Can Cui and Jiawei Wang and Eric Fagerberg and Chen, {Ping Min} and Connolly, {Kelli A.} and Martina Damo and Cheung, {Julie F.} and Tianyang Mao and Askari, {Adnan S.} and Shuting Chen and Brittany Fitzgerald and Foster, {Gena G.} and Eisenbarth, {Stephanie C.} and Hongyu Zhao and Joseph Craft and Joshi, {Nikhil S.}",

note = "Funding Information: We thank the N.S.J. and J.C. laboratory members for reviewing the manuscript; Z. Chen, C. Yang, and N. Ruddle for helpful discussions; and W. Wei for important guidance on statistical analysis. We also thank the Yale Flow Cytometry Core, Yale Keck DNA Sequencing Facility, Yale School of Medicine Histology Facility, and NIH Tetramer Core Facility. SW HEL mice were kindly provided by Dr. Robert Brink. Figures 2 A, S4 B, S6 A, and S6B and the graphical abstract were created with https://www.biorender.com . This work was supported by grants from the NCI ( K22CA200912 and 1RO1CA237037-01A1 to N.S.J.), NIH ( R37AR40072 and AR074545 to J.C.), and Yale SPORE in Lung Cancer (1P50CA196530 1P50CA196530 to N.S.J. and J.C.) and a Pilot Grant from Yale Cancer Center (to N.S.J. and J.C.). C.C. was supported by the Gruber Science Fellowship and Richard K. Gershon Research Fellowship. J.F.C., K.A.C., and B.F. were supported by the Yale Immunobiology NIH T32 training grant ( 5T32AI007019 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = dec,

day = "9",

doi = "10.1016/j.cell.2021.11.007",

language = "English (US)",

volume = "184",

pages = "6101--6118.e13",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "25",

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Cui, C, Wang, J, Fagerberg, E, Chen, PM, Connolly, KA, Damo, M, Cheung, JF, Mao, T, Askari, AS, Chen, S, Fitzgerald, B, Foster, GG, Eisenbarth, SC, Zhao, H, Craft, J & Joshi, NS 2021, 'Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses', Cell, vol. 184, no. 25, pp. 6101-6118.e13. https://doi.org/10.1016/j.cell.2021.11.007

TY - JOUR

T1 - Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

AU - Cui, Can

AU - Wang, Jiawei

AU - Fagerberg, Eric

AU - Chen, Ping Min

AU - Connolly, Kelli A.

AU - Damo, Martina

AU - Cheung, Julie F.

AU - Mao, Tianyang

AU - Askari, Adnan S.

AU - Chen, Shuting

AU - Fitzgerald, Brittany

AU - Foster, Gena G.

AU - Eisenbarth, Stephanie C.

AU - Zhao, Hongyu

AU - Craft, Joseph

AU - Joshi, Nikhil S.

N1 - Funding Information: We thank the N.S.J. and J.C. laboratory members for reviewing the manuscript; Z. Chen, C. Yang, and N. Ruddle for helpful discussions; and W. Wei for important guidance on statistical analysis. We also thank the Yale Flow Cytometry Core, Yale Keck DNA Sequencing Facility, Yale School of Medicine Histology Facility, and NIH Tetramer Core Facility. SW HEL mice were kindly provided by Dr. Robert Brink. Figures 2 A, S4 B, S6 A, and S6B and the graphical abstract were created with https://www.biorender.com . This work was supported by grants from the NCI ( K22CA200912 and 1RO1CA237037-01A1 to N.S.J.), NIH ( R37AR40072 and AR074545 to J.C.), and Yale SPORE in Lung Cancer (1P50CA196530 1P50CA196530 to N.S.J. and J.C.) and a Pilot Grant from Yale Cancer Center (to N.S.J. and J.C.). C.C. was supported by the Gruber Science Fellowship and Richard K. Gershon Research Fellowship. J.F.C., K.A.C., and B.F. were supported by the Yale Immunobiology NIH T32 training grant ( 5T32AI007019 ). Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/12/9

Y1 - 2021/12/9

N2 - CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.

AB - CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.

KW - B cell

KW - CD8 T cell

KW - IL-21

KW - T follicular helper cell

KW - lung cancer

KW - neoantigen

UR - http://www.scopus.com/inward/record.url?scp=85120637571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85120637571&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.11.007

DO - 10.1016/j.cell.2021.11.007

M3 - Article

C2 - 34852236

AN - SCOPUS:85120637571

SN - 0092-8674

VL - 184

SP - 6101-6118.e13

JO - Cell

JF - Cell

IS - 25

ER -

Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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