Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade

• Published in: British journal of cancer Vol. 122; no. 8; pp. 1185 - 1193
• Main Authors: Mizumoto, Yuki, Hemmi, Hiroaki, Katsuda, Masahiro, Miyazawa, Motoki, Kitahata, Yuji, Miyamoto, Atsushi, Nakamori, Mikihito, Ojima, Toshiyasu, Matsuda, Kenji, Nakamura, Masaki, Hayata, Keiji, Fukuda-Ohta, Yuri, Sugiyama, Masanaka, Ohta, Tomokazu, Orimo, Takashi, Okura, Soichiro, Sasaki, Izumi, Tamada, Koji, Yamaue, Hiroki, Kaisho, Tsuneyasu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 631/250/251/1567; 631/67/1059/2325; Animals; Antigens - immunology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cancer vaccines; Cancer Vaccines - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Chemokines; Chemokines, C - immunology; Cross-Priming - immunology; Dendritic cells; Dendritic Cells - immunology; Drug Resistance; Epidemiology; Fusion protein; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Lymphocytes T; Major histocompatibility complex; Mice, Inbred C57BL; Molecular Medicine; Neoplasms, Experimental - therapy; Oncology; PD-1 protein; Peptides; Poly I-C - pharmacology; Polyinosinic:polycytidylic acid; Proteins; Tumors; Vaccines, Subunit - immunology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0757-2

Background Cancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1 + DCs), with high ability to support CD8 + T-cell responses. Methods We have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice. Results The fusion protein was delivered to XCR1 + DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8 + T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab. Conclusions Cancer Ag targeting to XCR1 + DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.