Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.886683
Keywords
mimotope; endogenous retrovirus; T cell receptor; antigen; melanoma
Categories
Funding
- Melanoma Research Alliance
- Koch Institute Support (core) Grant from the National Cancer Institute [P30-CA14051]
- Packard Foundation
- Pew Foundation
- V Foundation
- AACR-TESARO Career Development Award for Immuno-oncology Research [17-2047-BIRN]
- National Institutes of Health Biotechnology Training Program [5T32GM008334]
- National Science Foundation Graduate Research Fellowship
- Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award
- Ludwig Center at MIT's Koch Institute for Integrative Cancer Research
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This study characterized the CD8(+) T cell response to melanoma, identified a dominant tumor-associated antigen, and generated mimotopes that induced robust functional T cell responses with cross-reactivity to the endogenous antigen.
While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8(+) T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8(+) T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.
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