Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma

Michael T. Patterson; Adam L. Burrack; Yingzheng Xu; Grant H. Hickok; Zoe C. Schmiechen; Samuel Becker; Eduardo Cruz-Hinojoza; Patricia R. Schrank; Ainsley E. Kennedy; Maria M. Firulyova; Ebony A. Miller; Konstantin Zaitsev; Jesse W. Williams; Ingunn M. Stromnes

doi:10.1016/j.celrep.2023.112732

Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma

Michael T. Patterson, Adam L. Burrack, Yingzheng Xu, Grant H. Hickok, Zoe C. Schmiechen, Samuel Becker, Eduardo Cruz-Hinojoza, Patricia R. Schrank, Ainsley E. Kennedy, Maria M. Firulyova, Ebony A. Miller, Konstantin Zaitsev, Jesse W. Williams, Ingunn M. Stromnes

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

Abstract

Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCII^hi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCII^hi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.

Original language	English (US)
Article number	112732
Journal	Cell reports
Volume	42
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2023.112732
State	Published - Jul 25 2023

Bibliographical note

Funding Information:
We acknowledge the University of Minnesota Flow Cytometry Core and Research Animal Resource facility. M.T.P. is supported by an AHA predoctoral fellowship ( 903380 ). Z.C.S. is supported by a NIH T32 AG029796 followed by NIH F31CA275289 . M.M.F. was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement 075-15-2022-301 ). K.Z. was supported by the Priority 2030 Federal Academic Leadership Program . J.W.W. is supported by NIH R01AI165553 and AHA CDA 855022 . I.M.S. is supported by NIH R01CA249393 , R01CA255039 , and P01CA254849 ; Department of Defense PA200286 ; a PanCAN-AACR Catalyst Award ( 19-35-STRO ); and an American Cancer Society Institutional Research Grant ( 124166-IRG-58-001-55-IRG65 ).

Publisher Copyright:
© 2023 The Author(s)

Keywords

CCR2
CD4 T cells
CD40
CP: Cancer
CP: Immunology
IFNg
PD-L1
PDA
T cells
immunotherapy
macrophage
pancreatic cancer

UN SDGs

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

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10.1016/j.celrep.2023.112732

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Patterson, M. T., Burrack, A. L., Xu, Y., Hickok, G. H., Schmiechen, Z. C., Becker, S., Cruz-Hinojoza, E., Schrank, P. R., Kennedy, A. E., Firulyova, M. M., Miller, E. A., Zaitsev, K., Williams, J. W., & Stromnes, I. M. (2023). Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma. Cell reports, 42(7), Article 112732. https://doi.org/10.1016/j.celrep.2023.112732

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abstract = "Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCIIhi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCIIhi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.",

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AU - Patterson, Michael T.

AU - Burrack, Adam L.

AU - Xu, Yingzheng

AU - Hickok, Grant H.

AU - Schmiechen, Zoe C.

AU - Becker, Samuel

AU - Cruz-Hinojoza, Eduardo

AU - Schrank, Patricia R.

AU - Kennedy, Ainsley E.

AU - Firulyova, Maria M.

AU - Miller, Ebony A.

AU - Zaitsev, Konstantin

AU - Williams, Jesse W.

AU - Stromnes, Ingunn M.

N1 - Funding Information: We acknowledge the University of Minnesota Flow Cytometry Core and Research Animal Resource facility. M.T.P. is supported by an AHA predoctoral fellowship ( 903380 ). Z.C.S. is supported by a NIH T32 AG029796 followed by NIH F31CA275289 . M.M.F. was supported by the Ministry of Science and Higher Education of the Russian Federation (agreement 075-15-2022-301 ). K.Z. was supported by the Priority 2030 Federal Academic Leadership Program . J.W.W. is supported by NIH R01AI165553 and AHA CDA 855022 . I.M.S. is supported by NIH R01CA249393 , R01CA255039 , and P01CA254849 ; Department of Defense PA200286 ; a PanCAN-AACR Catalyst Award ( 19-35-STRO ); and an American Cancer Society Institutional Research Grant ( 124166-IRG-58-001-55-IRG65 ). Publisher Copyright: © 2023 The Author(s)

PY - 2023/7/25

Y1 - 2023/7/25

N2 - Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCIIhi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCIIhi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.

AB - Pancreatic ductal adenocarcinoma (PDA) orchestrates a suppressive tumor microenvironment that fosters immunotherapy resistance. Tumor-associated macrophages (TAMs) are the principal immune cell infiltrating PDA and are heterogeneous. Here, by employing macrophage fate-mapping approaches and single-cell RNA sequencing, we show that monocytes give rise to most macrophage subsets in PDA. Tumor-specific CD4, but not CD8, T cells promote monocyte differentiation into MHCIIhi anti-tumor macrophages. By conditional major histocompatibility complex (MHC) class II deletion on monocyte-derived macrophages, we show that tumor antigen presentation is required for instructing monocyte differentiation into anti-tumor macrophages, promoting Th1 cells, abrogating Treg cells, and mitigating CD8 T cell exhaustion. Non-redundant IFNγ and CD40 promote MHCIIhi anti-tumor macrophages. Intratumoral monocytes adopt a pro-tumor fate indistinguishable from that of tissue-resident macrophages following loss of macrophage MHC class II or tumor-specific CD4 T cells. Thus, tumor antigen presentation by macrophages to CD4 T cells dictates TAM fate and is a major determinant of macrophage heterogeneity in cancer.

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KW - CP: Immunology

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KW - PDA

KW - T cells

KW - immunotherapy

KW - macrophage

KW - pancreatic cancer

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ER -

Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma

Abstract

Bibliographical note

Keywords

UN SDGs

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