A vaccine targeting resistant tumours by dual T cell plus NK cell attack

Soumya Badrinath, Maxence O. Dellacherie, Aileen Li, Shiwei Zheng, Xixi Zhang, Miguel Sobral, Jason W. Pyrdol, Kathryn L. Smith, Yuheng Lu, Sabrina Haag, Hamza Ijaz, Fawn Connor-Stroud, Tsuneyasu Kaisho, Glenn Dranoff, Guo-Cheng Yuan, David J. Mooney and Kai W. Wucherpfennig ()
Additional contact information
Soumya Badrinath: Dana-Farber Cancer Institute
Maxence O. Dellacherie: Harvard University
Aileen Li: Harvard University
Shiwei Zheng: Dana-Farber Cancer Institute
Xixi Zhang: Dana-Farber Cancer Institute
Miguel Sobral: Harvard University
Jason W. Pyrdol: Dana-Farber Cancer Institute
Kathryn L. Smith: Dana-Farber Cancer Institute
Yuheng Lu: Dana-Farber Cancer Institute
Sabrina Haag: Dana-Farber Cancer Institute
Hamza Ijaz: Wyss Institute for Biologically Inspired Engineering, Harvard University
Fawn Connor-Stroud: Emory University
Tsuneyasu Kaisho: Wakayama Medical University
Glenn Dranoff: Dana-Farber Cancer Institute
Guo-Cheng Yuan: Dana-Farber Cancer Institute
David J. Mooney: Harvard University
Kai W. Wucherpfennig: Dana-Farber Cancer Institute

Nature, 2022, vol. 606, issue 7916, 992-998

Abstract: Abstract Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.

Date: 2022
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DOI: 10.1038/s41586-022-04772-4

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