Background In patients treated with immunotherapy, mechanisms underlying why some respond to or fail treatment are not fully understood. Higher tumor mutational burden is often correlated with better responses, because the immune system reacts more strongly against mutated antigens (versus self antigens) due to a higher affinity interaction with the T cell receptor. In adoptive T cell transfer therapy (ACT), engraftment and persistence of the T cells are critical to prolonged antitumor responses. It remains unclear whether the affinity of the interaction between tumor antigen and TCR alone impacts the engraftment and persistence of tumor-specific T cells post ACT.
Methods To simulate this clinical scenario in mice, we used two different melanoma models: 1) B16F10 expressing a low affinity peptide (mgp100 = i.e. tumor/self-antigen), or 2) B16F10 expressing a higher affinity peptide (hgp100), which represents a neoantigen-expressing tumor.1 Pmel-1 CD8+ T cells expressing a TCR that recognizes gp100 were adoptively transferred into mice bearing B16F10 melanoma.
Results We posited that the function and persistence of adoptively transferred pmel-1 T cells would be increased in mice with neoantigen- compared to self- antigen expressing tumors. Indeed, we found that pmel-1 were less exhausted as well as engrafted and persisted far better in mice bearing tumors expressing neoantigens. Moreover, these large subcutaneous hot tumors shrank post ACT treatment and the animals survived long-term. Beneficial outcome was correlated with the appearance of vitiligo. Importantly, these cured mice were protected when rechallenged with a secondary tumor even after an intravenous rechallenge, implicating this ACT treatment mediates durable memory responses.
Conclusions Herein, we underscore how tumor antigen affinity can drastically change T cell fate. Future work will concentrate in exploring in depth the correlation of less differentiated cytotoxic T cells treating neo/self-antigen expressing melanomas mimicking a clinical setting.
Hanada K, Yu Z, Chappell GR, Park AS, Restifo NP. An effective mouse model for adoptive cancer immunotherapy targeting neoantigens. JCI Insight 2019;4(10).
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