No abstract

As a cell-based cancer vaccine, dendritic cells (DCs), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDCs), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1s) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared anti-tumor responses induced by GMDCs and cDC1 in Irf8 +32-/- mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8+ T cells in vitro. However, injection of GMDCs into tumors in Irf8 +32-/- mice did not induce anti-tumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 +32-/- mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce anti-tumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for anti-tumor therapy.

No abstract

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 −165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 −165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.

Supplementary Figure from cDC1 Vaccines Drive Tumor Rejection by Direct Presentation Independently of Host cDC1

Supplementary Figure from cDC1 Vaccines Drive Tumor Rejection by Direct Presentation Independently of Host cDC1

The events that initiate autoimmune diabetes in nonobese diabetic (NOD) mice remain poorly understood. CD4 + and CD8 + T cells are both required to develop disease, but their relative roles in initiating disease are unclear. To test whether CD4 + T cell infiltration into islets requires damage to β cells induced by autoreactive CD8 + T cells, we inactivated Wdfy4 in nonobese diabetic (NOD) mice (NOD. Wdfy4 −/−- ) using CRISPR/Cas9 targeting to eliminate cross-presentation by type 1 conventional dendritic cells (cDC1s). Similar to C57BL/6 Wdfy4 −/− mice, cDC1 in NOD. Wdfy4 −/− mice are unable to cross-present cell-associated antigens to prime CD8 + T cells, while cDC1 from heterozygous NOD. Wdfy4 +/− mice cross-present normally. Further, NOD. Wdfy4 −/− mice fail to develop diabetes while heterozygous NOD. Wdfy4 +/− mice develop diabetes similarly to wild-type NOD mice. NOD. Wdfy4 −/− mice remain capable of processing and presenting major histocompatibility complex class II (MHC-II)-restricted autoantigens and can activate β cell-specific CD4 + T cells in lymph nodes. However, disease in these mice does not progress beyond peri-islet inflammation. These results indicate that the priming of autoreactive CD8 + T cells in NOD mice requires cross-presentation by cDC1. Further, autoreactive CD8 + T cells appear to be required not only to develop diabetes, but to recruit autoreactive CD4 + T cells into islets of NOD mice, perhaps in response to progressive β cell damage.

<div>Abstract<p>As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in <i>Irf8</i> +32^–/– mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8⁺ T cells <i>in vitro</i>. However, injection of GMDCs into tumors in <i>Irf8</i> +32^–/– mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in <i>Irf8</i> +32^–/– mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8⁺ T cells, and rejection of the tumors. Tumor rejection did not require the <i>in vitro</i> loading of cDC1 with antigens, indicating that acquisition of antigens <i>in vivo</i> is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy.</p><p><i><a href="https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-22-0473" target="_blank">See related Spotlight by Hubert et al., p. 918</a></i></p></div>