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An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection.


ABSTRACT: Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection and, independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes that have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. These results from a single mouse model were validated in another antigenically distinct mouse cancer model and are consistent with data reported in human studies. Structural modeling showed how the MHC I-presented neoepitopes had an altered conformation, higher stability, or increased exposure to T cell receptors as compared with the unmutated counterparts. T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for generation of personalized human cancer vaccines.

SUBMITTER: Brennick CA 

PROVIDER: S-EPMC7843235 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection.

Brennick Cory A CA   George Mariam M MM   Moussa Marmar M MM   Hagymasi Adam T AT   Seesi Sahar Al SA   Shcheglova Tatiana V TV   Englander Ryan P RP   Keller Grant Lj GL   Balsbaugh Jeremy L JL   Baker Brian M BM   Schietinger Andrea A   Mandoiu Ion I II   Srivastava Pramod K PK  

The Journal of clinical investigation 20210201 3


Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection and, independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes that have strikingly different properties from conventional epitopes and sugge  ...[more]

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