T Cell Responses to Tumor Neoantigens: Evidence for Dominant and Subdominant Neoepitopes
Matthew M. Gubin, Jeffrey P. Ward, Cora Arthur, Maxim Artyomov, and Robert D. Schreiber
Washington University School of Medicine, Saint Louis, Missouri, USA
Monoclonal antibody (mAb) blockade of immune checkpoints such as PD-1 and CTLA-4 can stimulate therapeutic, T cell-dependent anti-tumor activity in mice and humans. We previously developed a method using exome sequencing and epitope prediction algorithms to reliably predict MHC class I cancer neoantigens. In the progressively growing mouse methylcholanthrene (MCA)-sarcoma line T3 two neoantigens [from point mutations in Laminin α subunit 4 (Lama4) and a glucosyltransferase called Alg8] were identified and demonstrated to be targeted by T cells activated by anti-PD-1 or anti-CTLA-4 mAbs. The relevance of mutant Lama4 (mLama4) and mutant Alg8 (mAlg8) was validated by several in vivo studies. Importantly prophylactic or therapeutic vaccination with mLama4 plus mAlg8 synthetic long peptides (SLP) resulted in rejection of T3 cells. The therapeutic protection provided by the SLP vaccine was equal to that afforded by checkpoint blockade therapy. Since we did not see evidence of T cell responses to any other neoantigens, we then explored whether the immunodominant antigens masked responses to other neoantigens. Using CRISPR/Cas9, we introduced point mutations to revert mLama4 and mAlg8 in T3 back to their nonimmunogenic wild type (WT) counterparts. T3 tumor cells with either mLama4 or mAlg8 reverted to WT were still susceptible to anti-PD-1 or anti-CTLA-4 immune-mediated control with skewing of the T cell response in the tumor towards the remaining neoantigen. Additionally, T3 tumor cells with both neoantigens reverted to WT were still susceptible to anti-PD-1 or anti-CTLA-4 immunotherapy but now the T cell responses were directed to subdominant neoantigens that were barely detectable against WT tumor cells. We are currently testing whether SLP vaccines comprised of subdominant neoantigens still present in fixed T3 tumor cells can protect mice against tumor growth. This system will allow us to address the many questions surrounding poorly understood phenomenon of immunodominance and how this may influence patient-specific personalized cancer immunotherapy directed against neoantigens.
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