Frontiers in Immunology (Jun 2022)
Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma
- Beth E. Grace,
- Beth E. Grace,
- Coralie M. Backlund,
- Coralie M. Backlund,
- Duncan M. Morgan,
- Duncan M. Morgan,
- Byong H. Kang,
- Byong H. Kang,
- Nishant K. Singh,
- Nishant K. Singh,
- Nishant K. Singh,
- Brooke D. Huisman,
- Brooke D. Huisman,
- C. Garrett Rappazzo,
- C. Garrett Rappazzo,
- Kelly D. Moynihan,
- Kelly D. Moynihan,
- Laura Maiorino,
- Laura Maiorino,
- Connor S. Dobson,
- Connor S. Dobson,
- Taeyoon Kyung,
- Taeyoon Kyung,
- Khloe S. Gordon,
- Khloe S. Gordon,
- Patrick V. Holec,
- Patrick V. Holec,
- Overbeck C. Takou Mbah,
- Daniel Garafola,
- Shengwei Wu,
- J. Christopher Love,
- J. Christopher Love,
- J. Christopher Love,
- K. Dane Wittrup,
- K. Dane Wittrup,
- K. Dane Wittrup,
- Darrell J. Irvine,
- Darrell J. Irvine,
- Darrell J. Irvine,
- Michael E. Birnbaum,
- Michael E. Birnbaum,
- Michael E. Birnbaum
Affiliations
- Beth E. Grace
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Beth E. Grace
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Coralie M. Backlund
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Coralie M. Backlund
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Duncan M. Morgan
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Duncan M. Morgan
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Byong H. Kang
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Byong H. Kang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Nishant K. Singh
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Nishant K. Singh
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Nishant K. Singh
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- Brooke D. Huisman
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Brooke D. Huisman
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- C. Garrett Rappazzo
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- C. Garrett Rappazzo
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Kelly D. Moynihan
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Kelly D. Moynihan
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Laura Maiorino
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Laura Maiorino
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Connor S. Dobson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Connor S. Dobson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Taeyoon Kyung
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Taeyoon Kyung
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Khloe S. Gordon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Khloe S. Gordon
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Patrick V. Holec
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Patrick V. Holec
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Overbeck C. Takou Mbah
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- Daniel Garafola
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Shengwei Wu
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- J. Christopher Love
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- J. Christopher Love
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- J. Christopher Love
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- K. Dane Wittrup
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- K. Dane Wittrup
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- K. Dane Wittrup
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Darrell J. Irvine
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Darrell J. Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Darrell J. Irvine
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- Michael E. Birnbaum
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Michael E. Birnbaum
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Michael E. Birnbaum
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2022.886683
- Journal volume & issue
-
Vol. 13
Abstract
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.
Keywords
