title: 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 withMycobacterium 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.
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand ; Victoria University of Wellington ; Wellington, New Zealand.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuhn
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand.
authors.forename: Jianping
authors.initials: J
authors.lastname: Yang
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand.
authors.forename: Evelyn J
authors.initials: EJ
authors.lastname: Hyde
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand.
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand ; Current address: Department of Microbiology; University of Otago ; Dunedin, New Zealand.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Kirman
authors.affiliation: Malaghan Institute of Medical Research ; Wellington, New Zealand.
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
keywords: CD4+ T cells; IL-1β; PD-1; monosodium urate crystals; mycobacteria; poly I:C; regulatory T cells; tumor immunotherapy