The ability of T cells to distinguish cancer cells from healthy body cells is an obvious conditio sine qua non for effective T cell-based cancer immunotherapies. However, for many years the molecular basis of such selective recognition has remained a matter of dispute. We have previously set out to shed light on this issue through the design of technologies for high-througput analysis of antigen reactivity of both cytotoxic (CD8) and helper (CD4) T cells. In subsequent work, we have used these technologies to demonstrate that T cell reactivity against the neoantigens that arise as a consequence of DNA damage is present in a large fraction of tumors with high mutational burdens, such as melanoma. Furthermore, we have demonstrated that such T cell recognition of neoantigens can be boosted by both immune checkpoint blockade and TIL therapy. Together, this work has provided significant evidence that the activity of therapies that boost endogenous tumor-specific T cell responses relies to a substantial extent on neoantigen recognition. Furthermore, the observed relationship between tumor mutational burden and response to immune checkpoint blockade observed by others and us provides additional support for this model.
With the now widespread evidence for a dominant role of cancer neoantigens in T cell control of cancer, a next challenge will be to devise clinically applicable strategies to selectively boost neoantigen-specific T cell reactivity (see Haanen lab).
Selected reading: Toebes, Nat Med 2006; Hadrup, Nat Methods 2009; van Rooij, J Clin Oncol 2013; Rizvi, Science 2015; Linnemann, Nat Med 2015; Verdegaal, Nature 2016; Schumacher Ann Rev Immunol 2019