Analysis of CD8 T cell receptor reactivities against a dominant tumor neoantigen reveals critical features required for effective cancer immunotherapy 2151

Description Accumulated mutations within tumor cells can generate neoantigens capable of inducing anti-tumor CD4 and CD8 T cell responses. While neoantigen diversity leads to the infiltration of a polyclonal T cell population within the tumor, even a single neoantigenic peptide can induce the priming of a variety of T cell clonotypes with unique T cell receptors. Identifying T cell clonotypes with the greatest anti-tumor activity could help guide the development of engineered T cell therapies. In this study, we used a well-characterized mouse sarcoma model (T3) and analyzed the evolution of CD8 T cell clonotypes against the dominant H2-kb restricted neoantigen epitope (mLama4) over time. We found that mLama4-specific CD8 T cells expressing TCR clonotypes with high tumor-killing capacity infiltrate tumors shortly after priming and expand in response to checkpoint blockade at the expense of clones that are less effective in tumor control. T cell migration post-infiltration of the dominant CD8 T cell clones (∼ day 9 post tumor inoculation) is dispensable for effective immune checkpoint therapy, suggesting that CD8 T cells that are sufficient for tumor killing rapidly expand and accumulate in growing tumors. Testing the dominant mLama4-specific CD8 clonotypes in an adoptive cell therapy system allowed us to compare highly functional clones, identifying those with higher peptide reactivity as preferred candidates for engineered T cell therapies.