CD4+T cells drive an inflammatory, TNF-a/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

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

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CD4+T cells drive an inflammatory, TNF-a/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, …

Cell Reports, Vol.41(13), 111874

Elsevier

2022

DOI: https://doi.org/10.1016/j.celrep.2022.111874

PMID: 36577370

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Abstract

Cell Biology

Life Sciences & Biomedicine

Science & Technology

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-a). 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-a, IFNg, and poly(I:C). Thus, a CD4+ T cell-inflamed pretreatment tumor microenvironment is necessary for response to chemotherapy, and this state can be therapeutically attained by targeted immunotherapy.

Details

Title: CD4+T cells drive an inflammatory, TNF-a/IFN-rich tumor microenvironment responsive to chemotherapy
Authors/Creators: Caitlin M. Tilsed - Institute for Respiratory Health
Nicola Principe - Institute for Respiratory Health
Joel Kidman - Institute for Respiratory Health
Wee Loong Chin - Sir Charles Gairdner Hospital
M. Lizeth Orozco Morales - Natl Ctr Asbestos Related Dis, Nedlands, WA 6009, Australia
Rachael M. Zemek - The Kids Research Institute Australia
Jonathan Chee - Institute for Respiratory Health
Rasa Islam - Asbestos Diseases Research Institute
Vanessa S. Fear - The Kids Research Institute Australia
Catherine Forbes - The Kids Research Institute Australia
Wayne J. Aston - Asbestos Diseases Research Institute
Maud Jansen - Natl Ctr Asbestos Related Dis, Nedlands, WA 6009, Australia
Abha Chopra - Murdoch University
Timo Lassmann - The Kids Research Institute Australia
Anna K. Nowak - Natl Ctr Asbestos Related Dis, Nedlands, WA 6009, Australia
Scott A. Fisher - Institute for Respiratory Health
Richard A. Lake - Institute for Respiratory Health
W. Joost Lesterhuis - The Kids Research Institute Australia
Publication Details: Cell Reports, Vol.41(13), 111874
Publisher: Elsevier
Grant note: Raine Research Foundation iCare Dust Diseases Board Cancer Council WA; Cancer Council Western Australia Simon Lee Foundation WA Department of Health NHMRC; National Health and Medical Research Council (NHMRC) of Australia UWA
Identifiers: 991005592876607891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Report

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.6 Immunology; 1.6.214 Checkpoint Inhibition
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics