Tilsed et al. showed that a monoclonal mesothelioma cell line grown subcutaneously in syngeneic mice responded dichotomously to cyclophosphamide (CTX). The pre- and post-treatment TMEs of CTX responder, but not progressor tumors were inflamed, expressing a CD4+ T cell, IFN-I/II, TNFα gene signature. Tumor response to CTX was reversed by depleting host CD4+ T (or CD8+ T) cells prior to tumor inoculation. The responder TME gene signature was associated with response to CTX-based chemotherapy in multiple breast cancer clinical trials. Intratumoral injection of TNFα, IFNγ and poly(I:C) (an inducer of IFN-I) improved subsequent response to CTX and 5-FU therapy.
Contributed by Paula Hochman
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.
Author Info: (1) National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; Instit
Author Info: (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; School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; Institute for Respiratory Health, Perth, WA 6101, 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. (4) 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. (5) 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. (6) Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia. (7) 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. (8) National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia. (9) Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia. (10) Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia. (11) National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia. (12) National Centre for Asbestos Related Diseases, Nedlands, WA 6009, Australia. (13) Institute of Immunology and Infectious Diseases, Murdoch University, Murdoch, WA 6150, Australia. (14) Telethon Kids Institute, University of Western Australia, West Perth, WA 6872, Australia. (15) 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. (16) 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. (17) 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. (18) 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.
