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

Cell Rep. 2022 Dec 27;41(13):111874. doi: 10.1016/j.celrep.2022.111874.

Authors

Caitlin M Tilsed¹, Nicola Principe¹, Joel Kidman¹, Wee Loong Chin², M Lizeth Orozco Morales³, Rachael M Zemek⁴, Jonathan Chee¹, Rasa Islam⁵, Vanessa S Fear⁴, Catherine Forbes⁴, Wayne J Aston⁵, Maud Jansen⁵, Abha Chopra⁶, Timo Lassmann⁴, Anna K Nowak⁷, Scott A Fisher¹, Richard A Lake¹, W Joost Lesterhuis⁸

Affiliations

¹ National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; Institute for Respiratory Health, Perth, WA 6101, Australia.
² National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; Medical School, University of Western Australia, Crawley, WA 6009, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
³ National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; Institute for Respiratory Health, Perth, WA 6101, Australia; Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia.
⁴ Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia.
⁵ National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia.
⁶ Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia.
⁷ National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; Institute for Respiratory Health, Perth, WA 6101, Australia; Medical School, University of Western Australia, Crawley, WA 6009, Australia; Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia.
⁸ National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; Institute for Respiratory Health, Perth, WA 6101, Australia; Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia. Electronic address: willem.lesterhuis@uwa.edu.au.

PMID: 36577370
DOI: 10.1016/j.celrep.2022.111874

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; CP: Cancer; chemotherapy; cyclophosphamide; immunotherapy; interferons; tumor microenvironment; tumor necrosis factor alpha.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD4-Positive T-Lymphocytes / metabolism
Cyclophosphamide / metabolism
Cyclophosphamide / pharmacology
Cyclophosphamide / therapeutic use
Mice
Neoplasms* / pathology
T-Lymphocytes*
Tumor Microenvironment
Tumor Necrosis Factor-alpha / metabolism

Substances

Tumor Necrosis Factor-alpha
Cyclophosphamide