Recent Progress in Dendritic Cell-Based Cancer Immunotherapy

Abstract

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.

Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

“…Upon encounter with cognate antigenic peptides presented by mature DCs, antigen-specific naïve T cells proliferate and differentiate into various effector T cell subsets in accordance with the local cytokine milieu, whereas memory T cells start rapid expansions for recall immune responses [ 21 ]. Furthermore, conventional DCs have two subtypes known as type 1 (cDC1s) and type 2 (cDC2s) [ 22 ]. It is now known that cDC1s preferentially induce the differentiation of naïve CD4 + T cells and CD8 + T cells into Th1 cells and CTLs, respectively [ 3 , 16 , 17 ], whereas cDC2s preferentially induce the differentiation of naïve CD4 + T cells into Th2 cells and Th17 cells ( Figure 1 ) [ 3 , 16 , 17 ].…”

“…It is now known that cDC1s preferentially induce the differentiation of naïve CD4 + T cells and CD8 + T cells into Th1 cells and CTLs, respectively [ 3 , 16 , 17 ], whereas cDC2s preferentially induce the differentiation of naïve CD4 + T cells into Th2 cells and Th17 cells ( Figure 1 ) [ 3 , 16 , 17 ]. Importantly, cDC1s selectively express XCR1 and are the most efficient DCs in the cross-presentation of exogenous antigens to CD8 + T cells [ 22 ]. Of note, while cDC1s activate CCR7-expressing naïve CD8 + T cells [ 22 ], activated CD8 + T cells in turn produce XCL1, the ligand of XCR1 ( Figure 1 ) [ 22 ].…”

“…Importantly, cDC1s selectively express XCR1 and are the most efficient DCs in the cross-presentation of exogenous antigens to CD8 + T cells [ 22 ]. Of note, while cDC1s activate CCR7-expressing naïve CD8 + T cells [ 22 ], activated CD8 + T cells in turn produce XCL1, the ligand of XCR1 ( Figure 1 ) [ 22 ]. This further promotes the interactions of CD8 + T cells and cDC1s, leading to full differentiation of effector CTLs [ 22 ].…”

“…Of note, while cDC1s activate CCR7-expressing naïve CD8 + T cells [ 22 ], activated CD8 + T cells in turn produce XCL1, the ligand of XCR1 ( Figure 1 ) [ 22 ]. This further promotes the interactions of CD8 + T cells and cDC1s, leading to full differentiation of effector CTLs [ 22 ]. In secondary immune responses, mature DCs also produce CCL3, CCL4, CCL5, CCL17, CCL22, CXCL9, CXCL10, and CXCL11 [ 22 ].…”

“…This further promotes the interactions of CD8 + T cells and cDC1s, leading to full differentiation of effector CTLs [ 22 ]. In secondary immune responses, mature DCs also produce CCL3, CCL4, CCL5, CCL17, CCL22, CXCL9, CXCL10, and CXCL11 [ 22 ]. Since Th1 cells express CCR5 and CXCR3, while Th2 cells, Th17 cells, and Treg cells express CCR4 [ 22 ], these chemokine–chemokine receptor axes contribute to the rapid expansion of effector T cells ( Figure 1 ).…”