Analysis of immune cell landscape in glioblastoma of CD4+ T cell-specific Atg5-deficient mice

Abstract

Autophagy is a conserved catabolic mechanism involving the lysosomal degradation of disposable or harmful cytoplasmic materials. Although the roles of autophagy in the immune system have been widely studied, the functions of autophagy in CD4+ T cells are subset- and disease-specific. Glioblastoma multiforme (GBM) is the most common and lethal form of brain tumor in adults and is often diagnosed as grade-4 tumors according to the World Health Organization classifications. Chloroquine, an autophagy inhibitor, has been used in clinical trials for GBM patients. However, the underlying mechanism of how autophagy inhibition modulates tumor-infiltrating CD4+ T cells to orchestrate antitumor immune responses against GBM remains unclear. Here, I demonstrate that CD4+ T cell-specific Atg5-deficient mice have prolonged survival in a mouse model of GBM. Furthermore, these mice have decreased numbers of tumor-infiltrating Tregs and an increased proportion of tumor-infiltrating CD4+ T cells that express high levels of IFN-gamma. The status of CD4+ T cells is critical for modulating antitumor immune responses against GBM regarding CD8+ T-cell and NK-cell responses, macrophage polarization, and antigen presentation. Collectively, my data reveal that enhancing Th1-cell responses with defective Tregs is a promising novel therapeutic intervention for GBM immunotherapy. Therefore, GBM patients could benefit from an autophagy blockade that not only targets tumor cells but also strengthens antitumor immune responses by the CD4+ T-cell modulation.