Are Conventional Type 1 Dendritic Cells Critical for Protective Antitumor Immunity and How?

Abstract

Dendritic cells (DCs) are endowed with a unique potency to prime T cells, as well as to orchestrate their expansion, functional polarization and effector activity in non-lymphoid tissues or in their draining lymph nodes. The concept of harnessing DC immunogenicity to induce protective responses in cancer patients was put forward about 25 years ago and has led to a multitude of DC-based vaccine trials. However, until very recently, objective clinical responses were below expectations. Conventional type 1 DCs (cDC1) excel in the activation of cytotoxic lymphocytes including CD8⁺ T cells (CTLs), natural killer (NK) cells, and NKT cells, which are all critical effector cell types in antitumor immunity. Efforts to investigate whether cDC1 might orchestrate immune defenses against cancer are ongoing, thanks to the recent blossoming of tools allowing their manipulation in vivo. Here we are reporting on these studies. We discuss the mouse models used to genetically deplete or manipulate cDC1, and their main caveats. We present current knowledge on the role of cDC1 in the spontaneous immune rejection of tumors engrafted in syngeneic mouse recipients, as a surrogate model to cancer immunosurveillance, and how this process is promoted by type I interferon (IFN-I) effects on cDC1. We also discuss cDC1 implication in promoting the protective effects of immunotherapies in mouse preclinical models, especially for adoptive cell transfer (ACT) and immune checkpoint blockers (ICB). We elaborate on how to improve this process by in vivo reprogramming of certain cDC1 functions with off-the-shelf compounds. We also summarize and discuss basic research and clinical data supporting the hypothesis that the protective antitumor functions of cDC1 inferred from mouse preclinical models are conserved in humans. This analysis supports potential applicability to cancer patients of the cDC1-targeting adjuvant immunotherapies showing promising results in mouse models. Nonetheless, further investigations on cDC1 and their implications in anti-cancer mechanisms are needed to determine whether they are the missing key that will ultimately help switching cold tumors into therapeutically responsive hot tumors, and how precisely they mediate their protective effects.

Keywords: CD8+ T cells; NK cells; cancer immunosurveillance; clinical trials; conventional type 1 dendritic cells; immunotherapy; tumor; type I IFN.

Figure 1

cDC1 key functions in antitumor immunity. Tumor DAMPs and Ag are released upon immunogenic cell death. cDC1 selectively express Clec9A, which binds F-Actin exposed at the surface of necrotic cells, enabling intracellular trafficking of engulfed Ag into endosomes specialized in cross-presentation. cDC1 immunogenic maturation and cross-presentation is promoted by their cell-intrinsic responses to IFN-I. XCR1 and CCR5 expression by cDC1 may contribute to their recruitment by CTL/NK/NKT producing XCL1 and CCL4/5 and by tumor cells producing CCL4. Reciprocally, cDC1 produce CXCL9/10 for local recruitment of CTL/NK/NKT. cDC1 deliver positive co-stimulation and produce IL-12, IFN-β, and IL-15Rα/IL-15 promoting the survival and proper activation of NK and CTL. cDC1 promote Th1 induction and CD4⁺ T cell help delivery to CTLs through simultaneous presentation of Ag in association to MHC-I and MHC-II. CTLs, NK, NKT cells can mediate tumor killing/cell death. Immunosuppressive cells infiltrating the tumor (TAMs, MoDCs, MDSCs, and Tregs) can dampen cDC1, Th1, CTLs, NK, and NKT antitumor immune responses. DAMPs, danger associated molecular patterns; F-Actin, filamentous actin; ICD, immunogenic cell death; MDSCs, Myeloid-derived suppressor cells; MoDCs, Monocyte-derived dendritic cells; TAMs, Tumor associated macrophages; Tregs, Regulatory T cells.

Figure 2

cDC1 cancer immunosurveillance cycle. cDC1 traffic to hot tumor. They uptake cell-associated Ag in the tumor after immunogenic cell death, undergo immunogenic maturation, and traffic to the tumor-draining lymph node. cDC1 prime naïve CTLs and polarize them toward protective effector functions. CTLs expand and migrate to tumor where they can be attracted by chemokines secreted locally by cDC1. The tumor-associated cDC1 also sustain infiltrating CTL protective functions (expansion, maintenance, and memory recall). They might also prime naïve CTLs in situ. TdLN, Tumor draining lymph node.

Figure 3

Icy, Cold, and Warm tumors escape from cDC1 immunosurveillance. Icy tumors (Left) failed to induce adaptive immune responses. For example, tumors with WNT/β-Catenin signaling or COX elevated activity disrupt the chemokine axes required for local cDC1 recruitment. Impairment of CTL infiltration would occur downstream of the failure of cDC1 to infiltrate the tumor. Cold tumors (top) are poorly immunogenic and infiltrated but induce some level of adaptive immunity. Tumors product factors inhibiting cDC1 differentiation or promoting their tolerogenic over immunogenic maturation. This can potentially lead to CTL inhibition and induction of peripheral tolerance. Warm tumors (Right) express tumor neoAg and are infiltrated by cDC1 and CTLs but are ultimately not controlled. Cancer immunoediting leads to immune escape. cDC1 have undergone immunogenic maturation but contribute to CTL chronic activation and exhaustion. ACT or mAb immunotherapies could contribute to immune control in Cold and Warm tumors, and cDC1 could play a major role in these settings (bottom). ACT, Adoptive cell transfer; β-Cat, β-Catenin; COX1/2, Cyclo-oxygenase 1/2; iTreg, induced regulatory T cell; mAb, monoclonal antibodies; PGE₂, Prostaglandin E2.

Figure 4

Synthesis of various studies aiming at evaluating the prognosis value of the tumor infiltration by different immune cell types based on the analysis of the whole tumor gene expression profiles.