DCision-making in tumors governs T cell anti-tumor immunity

Abstract

The exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell-T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.

Fig. 1. Conventional dendritic cells coordinate CD4 and CD8 T cell anti-tumor immune responses.

Tumor cells may process and present tumor-specific or -associated antigens on MHC class I molecules through the MHC-I antigen processing pathway. CD8 T cells recognize tumor antigens presented by tumor cells and may secrete granzyme B (GrB) and perforin to mediate cytotoxicity toward tumor cells. In addition, dendritic cells (DCs), particularly the conventional DC1 (cDC1) subset, play several roles in helping CD4 and CD8 T cells to target tumors. 1 DCs may process and present or cross-present, shown in (a) tumor-derived MHC-I– and MHC-II–restricted tumor antigens to CD8 and CD4 T cells, respectively. T cells that can recognize tumor-specific neoantigens bind to the neoantigen peptide:MHC complex, and become activated, in a process termed T cell priming. 2 Activated CD4 T cells can “license” cDC1 cells through CD40:CD40L signals. 3 Subsequently, cDC1 cells can further enhance CD8 T cell activation. In addition to indirectly helping to boost CD8 responses through cDC1-mediated licensing, CD4 T cells can also provide direct help to augment CD8 T cell responses.

Fig. 2. The tumor microenvironment alters dendritic cell function.

The tumor microenvironment (TME) may inhibit dendritic cell (DC) functions, abrogating DCs’ ability to promote T cell responses. Tumor cells often upregulate the expression of CD47, which may inhibit DC presentation of antigens to T cells. In addition, the accumulated lipid and metabolites within the TME exhibit similar negative effects on DC antigen presentation. Moreover, the elevated concentrations of TGF-β and Wnt, as well as LXRα, promote DC migration to the tumor but block migration to the lymph nodes. Furthermore, the TME is rich in cytokines IL-6, IL-10, and TGF-β, as well as tumor-derived VEGF. These molecules inhibit DC maturation, altering their ability to initiate a T cell response.