Sending a Message: Use of mRNA Vaccines to Target the Tumor Immune Microenvironment

Abstract

While cancer immunotherapies have become central to treatment, challenges associated with the ability of tumors to evade the immune system remain significant obstacles. At the heart of this issue is the tumor immune microenvironment, the complex interplay of the tumor microenvironment and the immune response. Recent advances in mRNA cancer vaccines represent major progress towards overcoming some of the challenges posed by deleterious components of the tumor immune microenvironment. Indeed, major breakthroughs in mRNA vaccine technology, such as the use of replacement nucleotides and lipid nanoparticle delivery, led to the vital success of mRNA vaccine technology in fighting COVID-19. This has in turn generated massive additional interest and investment in the platform. In this review, we detail recent research in the nature of the tumor immune microenvironment and in mRNA cancer vaccines and discuss applications by which mRNA cancer vaccines, often in combination with various adjuvants, represent major areas of potential in overcoming tumor immune microenvironment-imposed obstacles. To this end, we also review current mRNA cancer vaccine clinical trials.

Keywords: cancer vaccines; combination therapy; dendritic cell; immunotherapy; mRNA; tumor immune microenvironment.

Figure 1

Several approaches may be used to administer cancer vaccines. These approaches can include mRNA, gene-based, peptide-based, viral/bacterial-based, cell-based, tumor lysate, or toll-like receptor (TLR) ligands. Each approach offers a unique set of benefits and limitations—including efficacy, side effects, safety, cost, and mode of delivery.

Figure 2

The TIM consists of tumor cells, immune cells, and cytokines. The interplay between the pro- and anti-tumorigenic properties within the TIM determines the tumor progression or regression. (A) M1 macrophages demonstrate anti-tumor effects via direct cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Furthermore, TH1 T cells can downregulate Treg differentiation via the secretion of IFN-γ. (B) In a pro-tumorigenic environment, adaptive immune responses support the activation of several pathways. The activation of DCs is inhibited by cytokines such as IL-10, hindering the initiation of the adaptive immune system. Similarly, the infiltration of tumors by Tregs leads to the suppression of both adaptive and innate immune responses. The release of cytokines such as IL-10 and TGF-β supports the propagation of Tregs within the TIM. Similarly, M2 macrophages contribute to tumorigenesis by promoting tumor invasion, dissemination, and angiogenesis by generating various cytokines, including IL-1, IL-8, TNF-α, MMP-9, MMP-2, and VEGF.