MIT engineers have introduced a novel method to enhance T-cell responses in mRNA vaccines, potentially resulting in more potent cancer vaccines and improved defenses against infectious diseases. Typically, vaccines stimulate antibodies and T cells by activating antigen-presenting cells like dendritic cells. This research, however, fortified the T-cell response using a new vaccine adjuvant. These adjuvants are mRNA molecules that encode genes to activate immune signaling pathways, thereby enhancing the T-cell response.<\/p>\n
Experiments in mice showed that this mRNA-encoded adjuvant allowed the immune system to eliminate most tumors entirely, either independently or alongside a tumor antigen. It also strengthened the T-cell response to vaccines for influenza and Covid-19. Daniel Anderson, a professor at MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, remarked on the significance of these adjuvants in boosting antigen-targeted T cells, which are crucial for attacking virally infected or cancerous cells.<\/p>\n
The study, published in Nature Biotechnology, was co-authored by MIT’s Daniel Anderson and Harvard’s Christopher Garris. Lead authors include Akash Gupta, now at the University of Houston, MIT’s Kaelan Reed, and Harvard’s Riddha Das. Robert Langer of MIT and Ralph Weissleder of Harvard also contributed. Vaccines that trigger the immune system to target tumors have potential in clinical trials, but responses vary among patients. The MIT-MGH team aimed to enhance these immune responses by delivering mRNA strands encoding IRF8 and NIK genes, which are crucial for antigen presentation.<\/p>\n
NIK is an enzyme that activates immune signaling pathways, while IRF8 programs dendritic cells to activate T cells effectively. These cells can digest antigens and present them to T cells, prompting an immune response. Gupta noted that dendritic cells showed a shift towards a cDC1 phenotype, crucial for a robust T-cell response. The researchers used lipid nanoparticles, similar to those in mRNA Covid vaccines, to deliver the mRNA to the spleen. There, the particles interact with antigen-presenting cells, driving them to mature and prompt an anti-tumor response.<\/p>\n
Within a few days, T-cell numbers increase, helping recognize and attack tumors. Das explained that their approach reprograms immune cells internally, allowing for a stronger anti-tumor response. The team tested these immune-modulating mRNAs in mouse cancer models, witnessing significant tumor growth reduction and, in many cases, complete eradication. This effect was observed even without specific cancer antigens, though responses improved with them.<\/p>\n
The mRNA adjuvant also bolstered responses to checkpoint blockade inhibitors, drugs that aid T cells in overcoming tumor defenses. Although these drugs don’t work for everyone, combining them with mRNA adjuvants might enhance their effectiveness. Garris noted that the adjuvants create a T cell\u2013friendly environment in tumors, aiding rejection. Additionally, the adjuvant improved responses to Covid and flu vaccines, eliciting a much stronger T-cell response in mice.<\/p>\n
The team plans to test this approach further in hopes of applying it to both cancer and infectious diseases. Anderson expressed optimism that these adjuvants could eventually benefit humans and enhance various vaccines. The research received funding from Sanofi, the National Institutes of Health, the Marble Center for Cancer Nanomedicine, and the Koch Institute Support Grant from the National Cancer Institute.<\/p>\n