Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment

Abstract

Dendritic cells (DCs) play a central role in the regulation of the balance between CD8 T cell immunity vs. tolerance to tumor antigens. Cross-priming, a process which DCs activate CD8 T cells by cross-presenting exogenous antigens, plays a critical role in generating anti-tumor CD8 T cell immunity. However, there are compelling evidences now that the tumor microenvironment (TME)-mediated suppression and modulation of tumor-infiltrated DCs (TIDCs) impair their function in initiating potent anti-tumor immunity and even promote tumor progression. Thus, DC-mediated cross-presentation of tumor antigens in tumor-bearing hosts often induces T cell tolerance instead of immunity. As tumor-induced immunosuppression remains one of the major hurdles for cancer immunotherapy, understanding how DCs regulate anti-tumor CD8 T cell immunity in particular within TME has been under intensive investigation. Recent reports on the Batf3-dependent type 1 conventional DCs (cDC1s) in anti-tumor immunity have greatly advanced our understanding on the interplay of DCs and CD8 T cells in the TME, highlighted by the critical role of CD103⁺ cDC1s in the cross-priming of tumor antigen-specific CD8 T cells. In this review, we will discuss recent advances in anti-tumor CD8 T cell cross-priming by CD103⁺ cDC1s in TME, and share perspective on future directions including therapeutic applications and memory CD8 T cell responses.

Keywords: CD103+ cDC1s; CD8 T cell immunity; anti-tumor immunity; cancer immunotherapy; cross-priming; tumor microenvironment.

Figure 1

cDC1s and priming of tumor-antigen-specific CD8 T cells in the tumor microenvironment (TME) and tumor-draining lymph nodes (tdLNs). Migratory CD103⁺ cDC1s in the TME take up tumor antigens (black dots), and transport tumor antigens to tdLN by migrating to the tdLN in a CCR7-dependent mechanism. Once in the tdLN, cross-presenting CD103⁺ cDC1s prime naive tumor antigen-specific CD8 T cells to become effector CD8 T cells. Cross-presenting CD103⁺ cDC1s also transfer tumor antigens to other resident myeloid cells including CD8α⁺ cDC1s that are also likely involved in priming naive CD8 T cells in tdLN. cDC1s in the TME produce CXCL9/10 to recruit primed effector CD8 T cells into TME, where they are re-stimulated by CD103⁺ cDC1s leading to the efficient killing of tumor cells. The function of other DCs such as pDCs and cDC2s in CD8 T cell priming is less understood.