Epitope mapping of spontaneous autoantibodies to anaplastic lymphoma kinase (ALK) in non-small cell lung cancer
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Mark M. Awad1,*, Cristina Mastini2,*, Rafael B. Blasco3, Luca Mologni4, Claudia Voena2, Lara Mussolin5, Stacy L. Mach1, Anika E. Adeni1, Christine A. Lydon1, Lynette M. Sholl6, Pasi A. Jänne1 and Roberto Chiarle2,3
1Lowe Center for Thoracic Oncology, Department of Medical Oncology, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
2Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
3Department of Pathology, Children’s Hospital, Harvard Medical School, Boston, MA, USA
4Department of Health Sciences, University of Milano-Bicocca, Milan, Italy
5Department of Women and Children’s Health, University of Padua, Padua, Italy
6Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
*These authors have contributed equally to this work
Mark M. Awad, email: [email protected]
Roberto Chiarle, email: [email protected]
Keywords: lung cancer, anaplastic lymphoma kinase, autoantibodies, immunotherapy
Received: January 31, 2017 Accepted: August 25, 2017 Published: September 23, 2017
The anaplastic lymphoma kinase (ALK) is recognized by the immune system as a tumor antigen, and preclinical evidence suggests that ALK-rearranged NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. In contrast to ALK-rearranged lymphomas, the frequency and clinical significance of spontaneous ALK immune responses in patients with ALK-rearranged NSCLCs are largely unknown. We developed an enzyme-linked immunosorbent assay (ELISA) to measure anti-ALK antibody levels and mapped specific peptide epitope sequences within the ALK cytoplasmic domain in patients with non-small cell lung cancer. The ELISA method showed good correlation with ALK antibody titers measured with a standard immunocytochemical approach. Strong anti-ALK antibody responses were detected in 9 of 53 (17.0%) ALK-positive NSCLC patients and in 0 of 38 (0%) ALK-negative NSCLC patients (P<0.01), and the mean antibody levels were significantly higher in ALK-positive than in ALK-negative NSCLC patients (P=0.02). Across individual patients, autoantibodies recognized different epitopes in the ALK cytoplasmic domain, most of which clustered outside the tyrosine kinase domain. Whether the presence of high ALK autoantibody levels confers a more favorable prognosis in this patient population warrants further investigation.
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