Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
CD4+ T cells are critical mediators of anti-tumor immunity and orchestrate a broad range of immune responses against cancer. Previous studies from our lab and others have demonstrated that, adoptive transfer of tumor specific CD4+ T cells to lymphopenic hosts led to eradication of established tumors in mice models. Accumulating evidence from preclinical and clinical studies also suggest that CD4+ T cells in combination with chemotherapy can control tumor progression and recurrence. However, the molecular and cellular mechanisms by which tumor reactive CD4+ T cells eliminate a wide variety of tumors are not completely understood.
In this project, we set out to study the mechanisms underlying the therapeutic effect of chemo-immunotherapy in the form of cyclophosphamide (CTX) and tumor specific CD4+ T cells. Recent studies have revealed that combined effect of Th-1 cytokines, IFN-γ and TNF, drive both murine and human cancer cells in to senescence. In the present study we wanted to examine the specific roles of IFN-γ and TNF-α in the setting of chemoimmunotherapy and the contribution of other immune cells in the tumor microenvironment to tumor rejection beside the donor CD4+ T cells.
In a mouse model of colorectal cancer, we found that host-derived interferon gamma (IFN-γ) and expression of IFN-γR are critical components of CD4+T cell-mediated tumor rejection, whereas depletion of NK cells and macrophages separately did not compromise the therapeutic effect of the CTX and CD4+T cells regimen. In addition, IFN-γ appeared to drive tumor senescence and apoptosis in vivo, leading to a curative outcome. Furthermore, we analyzed the global metabolic profiling of tumor tissues at different time points before and after chemoimmunotherapy.
Our data suggests that CD4+T cells reprogram the metabolic profiling in tumor, tipping the balance towards progressive tumor regression. These findings may provide new insights into mechanisms of tumor rejection by CD4+ T cells, and may help develop more effective anti-tumor strategies based on a rational combination of chemotherapy and anti-tumor CD4+ T cells.