CD4+ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy

Caitlin M. Tilsed; Nicola Principe; Joel Kidman; Wee Loong Chin; M. Lizeth Orozco Morales; Rachael M. Zemek; Jonathan Chee; Rasa Islam; Vanessa S. Fear; Catherine Forbes; Wayne J. Aston; Maud Jansen; Abha Chopra; Timo Lassmann; Anna K. Nowak; Scott A. Fisher; Richard A. Lake; W. Joost Lesterhuis

doi:10.1016/j.celrep.2022.111874

CD4⁺ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy

Caitlin M. Tilsed, Nicola Principe, Joel Kidman, Wee Loong Chin, M. Lizeth Orozco Morales, Rachael M. Zemek, Jonathan Chee, Rasa Islam, Vanessa S. Fear, Catherine Forbes, Wayne J. Aston, Maud Jansen, Abha Chopra, Timo Lassmann, Anna K. Nowak, Scott A. Fisher, Richard A. Lake, W. Joost Lesterhuis

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Abstract

While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4+ T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4+ T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.

Original language	English
Article number	111874
Number of pages	19
Journal	Cell Reports
Volume	41
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2022.111874
Publication status	Published - 27 Dec 2022

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Tilsed, C. M., Principe, N., Kidman, J., Chin, W. L., Orozco Morales, M. L., Zemek, R. M., Chee, J., Islam, R., Fear, V. S., Forbes, C., Aston, W. J., Jansen, M., Chopra, A., Lassmann, T., Nowak, A. K., Fisher, S. A., Lake, R. A., & Lesterhuis, W. J. (2022). CD4⁺ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy. Cell Reports, 41(13), Article 111874. https://doi.org/10.1016/j.celrep.2022.111874

@article{70a0e12d4c37469e80bbda405462ddee,

title = "CD4+ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy",

abstract = "While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4+ T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4+ T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.",

keywords = "CD4+ T cells, chemotherapy, CP: Cancer, cyclophosphamide, immunotherapy, interferons, tumor microenvironment, tumor necrosis factor alpha",

author = "Tilsed, {Caitlin M.} and Nicola Principe and Joel Kidman and Chin, {Wee Loong} and {Orozco Morales}, {M. Lizeth} and Zemek, {Rachael M.} and Jonathan Chee and Rasa Islam and Fear, {Vanessa S.} and Catherine Forbes and Aston, {Wayne J.} and Maud Jansen and Abha Chopra and Timo Lassmann and Nowak, {Anna K.} and Fisher, {Scott A.} and Lake, {Richard A.} and Lesterhuis, {W. Joost}",

year = "2022",

month = dec,

day = "27",

doi = "10.1016/j.celrep.2022.111874",

language = "English",

volume = "41",

journal = "Cell Reports",

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Tilsed, CM, Principe, N, Kidman, J, Chin, WL, Orozco Morales, ML , Zemek, RM , Chee, J, Islam, R, Fear, VS, Forbes, C, Aston, WJ, Jansen, M, Chopra, A, Lassmann, T , Nowak, AK , Fisher, SA , Lake, RA & Lesterhuis, WJ 2022, 'CD4⁺ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy', Cell Reports, vol. 41, no. 13, 111874. https://doi.org/10.1016/j.celrep.2022.111874

TY - JOUR

T1 - CD4+ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy

AU - Tilsed, Caitlin M.

AU - Principe, Nicola

AU - Kidman, Joel

AU - Chin, Wee Loong

AU - Orozco Morales, M. Lizeth

AU - Zemek, Rachael M.

AU - Chee, Jonathan

AU - Islam, Rasa

AU - Fear, Vanessa S.

AU - Forbes, Catherine

AU - Aston, Wayne J.

AU - Jansen, Maud

AU - Chopra, Abha

AU - Lassmann, Timo

AU - Nowak, Anna K.

AU - Fisher, Scott A.

AU - Lake, Richard A.

AU - Lesterhuis, W. Joost

PY - 2022/12/27

Y1 - 2022/12/27

N2 - While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4+ T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4+ T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.

AB - While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors. Responsive tumors have an inflammatory and highly immune infiltrated pre-treatment tumor microenvironment characterized by the enrichment of pathways associated with CD4+ T cells, interferons (IFNs), and tumor necrosis factor alpha (TNF-α). The same gene expression profile is associated with response to cyclophosphamide-based chemotherapy in patients with breast cancer. Finally, we demonstrate that tumors can be sensitized to cyclophosphamide and 5-FU chemotherapy by pre-treatment with recombinant TNF-α, IFNγ, and poly(I:C). Thus, a CD4+ T cell-inflamed pre-treatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.

KW - CD4+ T cells

KW - chemotherapy

KW - CP: Cancer

KW - cyclophosphamide

KW - immunotherapy

KW - interferons

KW - tumor microenvironment

KW - tumor necrosis factor alpha

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U2 - 10.1016/j.celrep.2022.111874

DO - 10.1016/j.celrep.2022.111874

M3 - Article

C2 - 36577370

AN - SCOPUS:85144342083

SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 13

M1 - 111874

ER -

CD4⁺ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy

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