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.

Keywords: XCL1; XCR1; adjuvant; cancer vaccine; chemokine; cytotoxic T-lymphocyte; dendritic cells.

Figure 1

Different subsets of dendritic cells.

Figure 2

Use of the XCL1-XCR1 axis for targeted delivery of antigens to cross-presenting cDC1s. (A) An XCL1 protein fused to antigens or an anti-XCR1 monoclonal antibody fused to antigens can bind and deliver antigens to XCR1⁺ cDC1s to enhance antigen-specific CD8⁺ CTL responses. (B) A stable and highly active form of XCL1 (XCL1-V21C/A59C) efficiently induces the accumulation of cross-presenting cDC1 in the injection site. Antigen-captured cDC1s then migrate to and stay in the draining lymph nodes. Thus, by selectively attracting cDC1s, the stable and highly active XCL1 is an excellent adjuvant for induction of antigen-specific CD8⁺ CTL responses. XCL1-V21C/A59C also induces long-term memory CD8⁺ CTL responses due to prolonged maintenance of antigen-captured cDC1s in the draining lymph nodes.