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

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.

Automated summary

This study characterizes the chemotherapy-responsive tumor microenvironment in mice through RNA sequencing analysis on tumors before and after chemotherapy. It reveals that responsive tumors have a highly immune infiltrated and inflammatory pre-treatment tumor microenvironment. The same gene expression profile is also associated with response to cyclophosphamide-based chemotherapy in breast cancer patients.