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

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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 languageEnglish
Article number111874
Number of pages19
JournalCell Reports
Issue number13
Publication statusPublished - 27 Dec 2022


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