Mota et al. demonstrated that the spontaneous ALK-specific T cell responses generated in mice with ALK+ lung tumors were insufficient to achieve an effective antitumor response and were not enhanced by ICIs. Vaccination with a single ALK peptide increased intratumoral ALK-specific CD8+ T cells, delayed tumor progression, eradicated lung tumors in combination with ALK TKIs, and prevented the metastatic spread to the brain. In vaccinated mice, tumors escaped due to reversible MHC-I downregulation. ALK immunogenic peptides were identified in the context of two frequent HLA molecules (HLA-A*02:01 and HLA-B*07:02) from human tumor samples.
Contributed by Shishir Pant
ABSTRACT: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is treated with ALK tyrosine kinase inhibitors (TKIs), but the lack of activity of immune checkpoint inhibitors (ICIs) is poorly understood. Here, we identified immunogenic ALK peptides to show that ICIs induced rejection of ALK(+) tumors in the flank but not in the lung. A single-peptide vaccination restored priming of ALK-specific CD8(+) T cells, eradicated lung tumors in combination with ALK TKIs and prevented metastatic dissemination of tumors to the brain. The poor response of ALK(+) NSCLC to ICIs was due to ineffective CD8(+) T cell priming against ALK antigens and is circumvented through specific vaccination. Finally, we identified human ALK peptides displayed by HLA-A*02:01 and HLA-B*07:02 molecules. These peptides were immunogenic in HLA-transgenic mice and were recognized by CD8(+) T cells from individuals with NSCLC, paving the way for the development of a clinical vaccine to treat ALK(+) NSCLC.
Author Info: (1) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (2) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (3) De
Author Info: (1) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (2) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (3) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (7) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (8) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (9) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (10) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (12) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (13) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (14) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Molecular Imaging Center, University of Torino, Torino, Italy. Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Torino, Italy. (15) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (16) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (17) Danish Cancer Society Research Center, Copenhagen, Denmark. Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. (18) Danish Cancer Society Research Center, Copenhagen, Denmark. Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. Department of Bioinformatics, Semmelweis University, Budapest, Hungary. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Computer Science, Metropolitan College, Boston University, Boston, MA, USA. Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (24) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (25) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Howard Hughes Medical Institute, Chevy Chase, MD, USA. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. (28) Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. (29) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (30) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. rafael.b.blasco@gmail.com. (31) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. roberto.chiarle@childrens.harvard.edu. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. roberto.chiarle@childrens.harvard.edu.
