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

Abstract

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.

Therapy of solid tumors using probiotic Symbioflor-2 - restraints and potential

“…The second phase is dominated by tumor-specific T cells, - mainly CD8 positive cytotoxic T cells [ 50 , 84 – 86 ]. Interestingly, such cells are already present in the tumor-bearing mice before BMTT.…”

Monocyte-Derived Dendritic Cells Are Essential for CD8+ T Cell Activation and Antitumor Responses After Local Immunotherapy

“…Treatment of established B16 melanomas with the immune-activating agents MSU + Msmeg delays tumor growth and increases survival ( 9 , 11 ). Treatment success requires adaptive immunity, in particular CD8 + T cells, and correlates with the accumulation of moDCs in dLN as early as 1 day after the first MSU + Msmeg treatment ( 9 ).…”

“…Our previous work compared several different treatments with immunostimulatory agents, including LPS, polyI:C ( 9 ), and CpG immunostimulatory oligonucleotides (unpublished data), to show that antitumor activity correlated with increased numbers of moDCs in the tumor dLN. In addition, treatments that were effective on B16 melanoma were also effective on EL4 thymomas ( 11 ) and 4T1 mammary carcinomas ( 9 ), suggesting that the requirement for moDCs in antitumor immune responses extends to other forms of immunotherapy besides MSU + Msmeg , and to multiple tumor models.…”

“…Several studies have shown that immunostimulating treatments that activate DCs also lead to induction of powerful CD8 + T effector cells that eliminate tumor cells and delay tumor growth ( 6 – 10 ). Unexpectedly, by carrying out a detailed study of the effects of these treatments on DC phenotype, we found that successful therapies do not simply activate existing DC subsets, but they also elicit the differentiation of monocytes into monocyte-derived DCs (moDCs) in the dLNs ( 9 , 11 , 12 ). Whether moDCs are simply passengers in the induced inflammatory response or powerful antigen-presenting cells that are especially suited to stimulating potent antitumor immunity remains unclear.…”

“…These cytokines were reported to play a key role in moDC generation and function ( 18 ). In addition, we observed that MSU + Msmeg induced the release of IL-1β, which was required for the antitumor response ( 11 ).…”