Underdog support

When they’re attacking tumors, T cells of the immune system typically target neoantigens—which are generated by the random mutations accumulated by cancer cells. But relatively little is known about the interplay between T cell responses to distinct neoantigens or how that influences tumor control. Researchers led by Ludwig MIT’s Tyler Jacks reported in a September paper in Cell their study of these questions in a mouse model of lung cancer. The T cell response in lung tumors, they found, is dominated by neoantigens that most stably bind the MHC protein, which presents the antigenic fragments to T cells. This antigen dominance can result in a failure to generate strong immune responses to subdominant antigens expressed in the same tumor. Further, while those suppressed, subdominant T cells express a protein, TCF1, associated with responses to immune checkpoint blockade (ICB) therapy, they also express proteins associated with T cell dysfunction. Tyler and his colleagues discovered that vaccinating mice with a subdominant neoantigen stimulated the production of highly functional T cells and shrank lung tumors in the mice. The researchers will be examining therapeutic approaches combining this vaccination strategy with ICB therapy.

This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).


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