Landscape of helper and regulatory antitumour CD4+ T cells in melanoma

Giacomo Oliveira (), Kari Stromhaug, Nicoletta Cieri, J. Bryan Iorgulescu, Susan Klaeger, Jacquelyn O. Wolff, Suzanna Rachimi, Vipheaviny Chea, Kate Krause, Samuel S. Freeman, Wandi Zhang, Shuqiang Li, David A. Braun, Donna Neuberg, Steven A. Carr, Kenneth J. Livak, Dennie T. Frederick, Edward F. Fritsch, Megan Wind-Rotolo, Nir Hacohen, Moshe Sade-Feldman, Charles H. Yoon, Derin B. Keskin, Patrick A. Ott, Scott J. Rodig, Genevieve M. Boland and Catherine J. Wu ()
Additional contact information
Giacomo Oliveira: Dana-Farber Cancer Institute
Kari Stromhaug: Dana-Farber Cancer Institute
Nicoletta Cieri: Dana-Farber Cancer Institute
J. Bryan Iorgulescu: Dana-Farber Cancer Institute
Susan Klaeger: Broad Institute of MIT and Harvard
Jacquelyn O. Wolff: Center for Immuno-Oncology, Dana-Farber Cancer Institute
Suzanna Rachimi: Broad Institute of MIT and Harvard
Vipheaviny Chea: Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute
Kate Krause: Massachusetts General Hospital
Samuel S. Freeman: Harvard Medical School
Wandi Zhang: Dana-Farber Cancer Institute
Shuqiang Li: Broad Institute of MIT and Harvard
David A. Braun: Dana-Farber Cancer Institute
Donna Neuberg: Dana-Farber Cancer Institute
Steven A. Carr: Broad Institute of MIT and Harvard
Kenneth J. Livak: Dana-Farber Cancer Institute
Dennie T. Frederick: Broad Institute of MIT and Harvard
Edward F. Fritsch: Dana-Farber Cancer Institute
Megan Wind-Rotolo: Bristol-Myers Squibb
Nir Hacohen: Harvard Medical School
Moshe Sade-Feldman: Broad Institute of MIT and Harvard
Charles H. Yoon: Dana-Farber Cancer Institute
Derin B. Keskin: Dana-Farber Cancer Institute
Patrick A. Ott: Dana-Farber Cancer Institute
Scott J. Rodig: Brigham and Women’s Hospital
Genevieve M. Boland: Harvard Medical School
Catherine J. Wu: Dana-Farber Cancer Institute

Nature, 2022, vol. 605, issue 7910, 532-538

Abstract: Abstract Within the tumour microenvironment, CD4+ T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules1,2, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4+ T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4+ T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4+ T regulatory (TReg) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4+ TReg clones were stimulated directly by HLA class II-positive melanoma and demonstrated specificity for melanoma neoantigens. This phenomenon was observed in the presence of an extremely high tumour neoantigen load, which we confirmed to be associated with HLA class II positivity through the analysis of 116 melanoma specimens. Our data reveal the landscape of infiltrating CD4+ T cells in melanoma and point to the presentation of HLA class II-restricted neoantigens and direct engagement of immunosuppressive CD4+ TReg cells as a mechanism of immune evasion that is favoured in HLA class II-positive melanoma.

Date: 2022
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DOI: 10.1038/s41586-022-04682-5

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