Tumor-released autophagosomes induces CD4+ T cell-mediated immunosuppression via a TLR2-IL-6 cascade

Background: CD4(+) T cells are critical effectors of anti-tumor immunity, but how tumor cells influence CD4(+) T cell effector function is not fully understood. Tumor cell-released autophagosomes (TRAPs) are being recognized as critical modulators of host anti-tumor immunity during tumor progression. Here, we explored the mechanistic aspects of TRAPs in the modulation of CD4(+) T cells in the tumor microenvironment. Methods: TRAPs isolated from tumor cell lines and pleural effusions or ascites of cancer patients were incubated with CD4(+) T cells to examine the function and mechanism of TRAPs in CD4(+) T cell differentiation and function. TRAPs-elicited CD+ T cells were tested for their suppression of effector T cell function, induction of regulatory B cells, and promotion of tumorigenesis and metastasis in a mouse model. Results: Heat shock protein 90 alpha (HSP90 alpha) on the surface of TRAPs from malignant effusions of cancer patients and tumor cell lines stimulated CD4(+) T cell production of IL-6 via a TLR2-MyD88-NF-kappa B signal cascade. TRAPs-induced autocrine IL-6 further promoted CD4(+) T cells secretion of IL-10 and IL-21 via STAT3. Notably, TRAPs-elicited CD4(+) T cells inhibited CD4(+) and CD8(+) effector T cell function in an IL-6- and IL-10-dependent manner and induced IL-10-producing regulatory B cells (Bregs) via IL-6, IL-10 and IL-21, thereby promoting tumor growth and metastasis. Consistently, inhibition of tumor autophagosome formation or IL-6 secretion by CD4(+) T- cells markedly retarded tumor growth. Furthermore, B cell or CD4(+) T cell depletion impeded tumor growth by increasing effector T cell function. Conclusions: HSP90 alpha on the surface of TRAPs programs the immunosuppressive functions of CD4(+) T cells to promote tumor growth and metastasis. TRAPs or their membrane-bound HSP90 alpha represent important therapeutic targets to reverse cancer-associated immunosuppression and improve immunotherapy.