MHC-II neoantigens shape tumour immunity and response to immunotherapy

Elise Alspach, Danielle M. Lussier, Alexander P. Miceli, Ilya Kizhvatov, Michel DuPage, Adrienne M. Luoma, Wei Meng, Cheryl F. Lichti, Ekaterina Esaulova, Anthony N. Vomund, Daniele Runci, Jeffrey P. Ward, Matthew M. Gubin, Ruan F. V. Medrano, Cora D. Arthur, J. Michael White, Kathleen C. F. Sheehan, Alex Chen, Kai W. Wucherpfennig, Tyler Jacks, Emil R. Unanue, Maxim N. Artyomov and Robert D. Schreiber ()
Additional contact information
Elise Alspach: Washington University School of Medicine
Danielle M. Lussier: Washington University School of Medicine
Alexander P. Miceli: Washington University School of Medicine
Ilya Kizhvatov: Washington University School of Medicine
Michel DuPage: Massachusetts Institute of Technology
Adrienne M. Luoma: Dana-Farber Cancer Institute
Wei Meng: Washington University School of Medicine
Cheryl F. Lichti: Washington University School of Medicine
Ekaterina Esaulova: Washington University School of Medicine
Anthony N. Vomund: Washington University School of Medicine
Daniele Runci: Washington University School of Medicine
Jeffrey P. Ward: Washington University School of Medicine
Matthew M. Gubin: Washington University School of Medicine
Ruan F. V. Medrano: Washington University School of Medicine
Cora D. Arthur: Washington University School of Medicine
J. Michael White: Washington University School of Medicine
Kathleen C. F. Sheehan: Washington University School of Medicine
Alex Chen: Washington University School of Medicine
Kai W. Wucherpfennig: Dana-Farber Cancer Institute
Tyler Jacks: Massachusetts Institute of Technology
Emil R. Unanue: Washington University School of Medicine
Maxim N. Artyomov: Washington University School of Medicine
Robert D. Schreiber: Washington University School of Medicine

Nature, 2019, vol. 574, issue 7780, 696-701

Abstract: Abstract The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting1. Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with cancer that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed2–4. Although the role of tumour neoantigen-specific CD8+ T cells in tumour rejection is well established5–9, the roles of other subsets of T cells have received less attention. Here we show that spontaneous and immunotherapy-induced anti-tumour responses require the activity of both tumour-antigen-specific CD8+ and CD4+ T cells, even in tumours that do not express major histocompatibility complex (MHC) class II molecules. In addition, the expression of MHC class II-restricted antigens by tumour cells is required at the site of successful rejection, indicating that activation of CD4+ T cells must also occur in the tumour microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumour response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore needs to be considered when identifying patients who will most benefit from immunotherapy.

Date: 2019
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DOI: 10.1038/s41586-019-1671-8

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