TY - JOUR
T1 - MHC-II neoantigens shape tumour immunity and response to immunotherapy
AU - Alspach, Elise
AU - Lussier, Danielle M.
AU - Miceli, Alexander P.
AU - Kizhvatov, Ilya
AU - DuPage, Michel
AU - Luoma, Adrienne M.
AU - Meng, Wei
AU - Lichti, Cheryl F.
AU - Esaulova, Ekaterina
AU - Vomund, Anthony N.
AU - Runci, Daniele
AU - Ward, Jeffrey P.
AU - Gubin, Matthew M.
AU - Medrano, Ruan F.V.
AU - Arthur, Cora D.
AU - White, J. Michael
AU - Sheehan, Kathleen C.F.
AU - Chen, Alex
AU - Wucherpfennig, Kai W.
AU - Jacks, Tyler
AU - Unanue, Emil R.
AU - Artyomov, Maxim N.
AU - Schreiber, Robert D.
N1 - Funding Information:
Acknowledgements We thank all members of the Schreiber laboratory for discussions and technical support. This work was supported by grants to R.D.S. from the National Cancer Institute of the National Institutes of Health (RO1CA190700), the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, Janssen Pharmaceutical Company of Johnson and Johnson and the Prostate Cancer Foundation, and by a Stand Up to Cancer-Lustgarten Foundation Pancreatic Cancer Foundation Convergence Dream Team Translational Research Grant. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. E.A. and D.M.L were supported by a postdoctoral training grant (T32 CA00954729) from the National Cancer Institute. D.M.L. and M.M.G. were supported by the Irvington Postdoctoral Fellowship from the Cancer Research Institute. M.D. is a St Baldrick’s Scholar with support from Hope with Hazel and a Pew-Stewart Scholar for Cancer Research supported by the Pew Charitable Trusts. J.P.W. is supported by the National Cancer Institute of the National Institutes of Health Paul Calabresi Career Development Award in Clinical Oncology (K12CA167540). M.M.G. is supported by a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy. K.W.W. receives support from the National Institutes of Health (R01CA238039). T.J. receives support from a National Institutes of Health Cancer Center Support Grant (P30CA14051) and the Howard Hughes Medical Institute. E.R.U. receives support from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (AI114551 and DK058177). Aspects of the studies, including ELISPOT, were performed by D. Bender at the Immunomonitoring Laboratory (IML), which is supported by the Andrew M. and Jane N. Bursky Center for Human Immunology and Immunotherapy Programs and the Alvin J. Siteman Comprehensive Cancer Center which, in turn, is supported by a National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (P30CA91842).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/10/31
Y1 - 2019/10/31
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074223743&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1671-8
DO - 10.1038/s41586-019-1671-8
M3 - Article
C2 - 31645760
AN - SCOPUS:85074223743
SN - 0028-0836
VL - 574
SP - 696
EP - 701
JO - Nature
JF - Nature
IS - 7780
ER -