Red blood cell-based vaccines for ameliorating cancer chemoimmunotherapy

Abstract

Immune checkpoint blockade (ICB) therapy has shown promising antitumor effects, but its immune response rate remains unsatisfactory. In recent years, chemotherapy has been proven to have synergistic effects with ICB therapy because some chemotherapeutic agents can enhance the immunogenicity of tumor cells by inducing immunogenic cell death (ICD). However, it cannot be ignored that chemotherapy often shows limited therapeutic efficacy due to high cytotoxicity, drug resistance, and some other side effects. Herein, we report a strategy to improve cancer immunotherapy by utilizing red blood cell-based vaccines (RBC-vaccines) where chemotherapy-induced tumor antigens (cAgs) are anchored onto red blood cells (RBCs) via the EDC/NHS-mediated amine coupling reaction. In this work, RBC-vaccines administered subcutaneously are primarily devoured by dendritic cells (DCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment by increasing the infiltration of intratumoral CD8⁺ and CD4⁺ T cells and elevating the intratumoral ratio of CD8⁺ T cells to regulatory T cells in the CT-26 colon cancer model. Finally, based on the rejection of tumor rechallenge in cured mice, the combination therapy of RBC-vaccines and αPD-1 can induce the expansion of memory T cells and thereby establish a long-term antitumor immune response. Taken together, the proposed RBC-vaccines have great potential to improve chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Immunotherapy, especially immune checkpoint blockade therapy, has made great contributions to the treatment of some advanced cancers. Unfortunately, the great majority of patients with cancer do not benefit from immunotherapy. To enhance the response rate of immunotherapy, we developed red blood cell-based vaccines (RBC-vaccines) against cancers where antigens were harvested from chemotherapy-treated cancer cells and then attached to erythrocytes via covalent surface modification. Such RBC-vaccines could provide a wide variety of tumor antigens and damage-associated molecular patterns without the use of any extra ingredients to trigger a stronger antitumor immune response. More importantly, the combination of RBC-vaccines with PD-1 blockade could significantly improve the efficacy of cancer immunotherapy and induce durable antitumor immunity.

Keywords: Chemoimmunotherapy; Chemotherapy-induced antigen; Immune checkpoint blockade; Red blood cell.