Enhancing the Efficacy of Tumor Vaccines Based on Immune Evasion Mechanisms

Abstract

Tumor vaccines aim to expand tumor-specific T cells and reactivate existing tumor-specific T cells that are in a dormant or unresponsive state. As such, there is growing interest in improving the durable anti-tumor activity of tumor vaccines. Failure of vaccine-activated T cells to protect against tumors is thought to be the result of the immune escape mechanisms of tumor cells and the intricate immunosuppressive tumor microenvironment. In this review, we discuss how tumor cells and the tumor microenvironment influence the effects of tumor infiltrating lymphocytes and summarize how to improve the efficacy of tumor vaccines by improving the design of current tumor vaccines and combining tumor vaccines with other therapies, such as metabolic therapy, immune checkpoint blockade immunotherapy and epigenetic therapy.

Keywords: combination therapies; immune evasion; immunotherapy; tumor microenvironment; tumor vaccines.

Figure 1

Regulation of T cells by tumors. The key aspects of how tumors influence the function of effector T cells are illustrated. 1) Abnormal alterations of MHC-I molecules in tumor cells can help evade the recognition of T cells. 2) A series of factors in TME can inhibit the maturation of APCs, thus defecting the priming and activating of effector T cells. 3) Tumor blood vessels act as physical barriers affecting the infiltration of T cells into the tumor bed. The vascular endothelial growth factors generated by tumor derived blood vessels can result in multiple changes within the vessels and thereby drive T cells depletion. 4) Abnormal cytokines and chemokines in TME can influence the infiltration of T cells. In tumors lacking in the infiltration of effector T cells, the expression of chemokines involved in the recruitment of T cells are significantly reduced. 5) Negative cellular components are key cellular mediators reshaping the immunosuppressive TME. 6) Dysregulated metabolism pathways in tumor cells can lead to insufficient nutrients in TME. What’s more, the specialized metabolism of tumor cells establishes an unfriendly TME to effector T cells, which further increases the living stress of effector T cells. 7) Effector T cells infiltrating in TME are frequently in exhaustion state and accumulating evidence implies such reprogramming to be the consequence of aberrant epigenomes such as methylated. TCR, T cell receptor; MHC-I, major histocompatibility class I molecules; APCs, antigen presenting cells; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells.