Clec9A+ Dendritic Cells Are Not Essential for Antitumor CD8+ T Cell Responses Induced by Poly I:C Immunotherapy

Abstract

In the steady state, tumors harbor several populations of dendritic cells (DCs) and myeloid cells that are key regulators of the intratumoral immune environment. Among these cells, migratory CD103 cross-presenting DCs are thought to be critical for tumor-specific CTL responses and tumor resistance. However, it is unclear whether this prominent role also extends to immunotherapy. We used a murine orthotopic mammary tumor model, as well as Clec9A-diphtheria toxin receptor mice that can be depleted of the specialized cross-presenting CD8α and CD103 DC1 subsets, to investigate the role of these DCs in immunotherapy. Treatment with monosodium urate crystals and mycobacteria at the tumor site delayed tumor growth and required DC1s for efficacy. In contrast, treatment with poly I:C was equally effective regardless of DC1 depletion. Neither treatment affected myeloid-derived suppressor cell numbers in the spleen or tumor. Similar experiments using subcutaneous B16 melanoma tumors in BATF3-knockout mice confirmed that CD103 DCs were not necessary for successful poly I:C immunotherapy. Nevertheless, adaptive immune responses were essential for the response to poly I:C, because mice depleted of CD8 T cells or all DC subsets were unable to delay tumor growth. In vivo experiments showed that DC1 and DC2 subsets were able to take up tumor Ags, with DC2s making up the larger proportion of lymph node DCs carrying tumor material. Both DC subsets were able to cross-present OVA to OT-I T cells in vitro. Thus, immunotherapy with poly I:C enables multiple DC subsets to cross-present tumor Ag for effective antitumor immune responses.

Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

“…Interestingly, perhaps related to our findings with sGsn -deficient mice, it has been reported that patients with Meretoja’s disease, in which proteolytic cleavage leads to loss of sGSN function, display a lower prevalence of fatal cancers ( Schmidt et al., 2016 ). Finally, irrespective of sGSN, it is important to note that cDC1s and/or DNGR-1-mediated cross-presentation might be dispensable for immunity to some cancer types ( Asano et al., 2011 ; Gilfillan et al., 2018 ; Ma et al., 2013 ).…”

The Role of Type 1 Conventional Dendritic Cells in Cancer Immunity

“…In the above-mentioned models, loss of BATF3-dependent cDC1 cannot be compensated by other DC subsets or through BATF3-independent cDC1 development, for example, through cytokine-mediated induction of BATF and BATF2 [15] . However, cDC1s appear redundant for the success of poly(I:C) therapy and anthracycline chemotherapy in some mouse tumor models, arguing that other cells can compensate for lack of cDC1 in certain instances 16 , 17 .

Human cDC1 In lymphoid and non-lymphoid organs, human cDC1s can be identified by BDCA3 expression and show a close relationship with mouse cDC1s at the gene expression level [9] .

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The Flt3L/Flt3 Axis in Dendritic Cell Biology and Cancer Immunotherapy

“…Here, a combination of Flt3L with TLR3 agonists improved the efficacy of anti-PDL1, anti-PD1 and anti-41BB [70,71,86]. However, in these reports, the precise contribution of Flt3L to the combination with immune checkpoint therapy is difficult to discern, because the antitumor effects of polyI:C do not rely on cDC1s [87]. Finally, Batf3-dependent cDC1s are also required for efficacious adoptive T cell transfer therapy [88,89].…”