IL-1βR-dependent priming of antitumor CD4(+) T cells and sustained antitumor immunity after peri-tumoral treatment with MSU and mycobacteria

Local immune-activating therapies seek to improve the presentation of tumor antigen, thereby promoting the activation of antitumor CD8(+) T cells and delaying tumor growth. Surprisingly, little is known about the ability of these therapies to stimulate antitumor CD4(+) T cells. We examined tumor-specific CD4(+) T cell responses after peri-tumoral administration of the TLR3 agonist polyinosinic-polycytidylic acid (poly I:C), or the danger signal monosodium urate crystals in combination with Mycobacterium smegmatis (MSU + Msmeg) in mice. Both treatments delayed tumor growth, however, only MSU + Msmeg induced proliferation of tumor-specific CD4(+) T cells in the draining lymph node (dLN). In line with the proliferation data, administration of MSU + Msmeg, but not poly I:C, enhanced the infiltration of CD4(+)FoxP3(−) T cells into the tumor, increased their capacity to produce IFNγ and TNF-α, and decreased PD-1 expression on tumor-infiltrating CD8(+) T cells. Induction of CD4(+) T cell proliferation by treatment with MSU + Msmeg required IL-1βR signaling, as it was blocked by administration of the IL-1βR antagonist Anakinra. In addition, treatment with Anakinra or with anti-CD4 also reversed the increased survival after tumor challenge in MSU + Msmeg treated mice. Thus, peri-tumoral treatment with MSU + Msmeg results in IL-1βR-dependent priming of antitumor CD4(+) T cells in the LN, with consequent superior activation of CD4(+) and CD8(+) T cells within the tumor, and sustained antitumor activity.