Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer

• Published in: Clinical cancer research Vol. 23; no. 15; pp. 4347 - 4353
• Main Authors: Assadipour, Yasmine, Zacharakis, Nikolaos, Crystal, Jessica S, Prickett, Todd D, Gartner, Jared J, Somerville, Robert P T, Xu, Hui, Black, Mary A, Jia, Li, Chinnasamy, Harshini, Kriley, Isaac, Lu, Lily, Wunderlich, John R, Zheng, Zhili, Lu, Yong-Chen, Robbins, Paul F, Rosenberg, Steven A, Goff, Stephanie L, Feldman, Steven A
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.08.2017
• Subjects: Antigen-presenting cells; Antigen-Presenting Cells - immunology; Breast cancer; Cancer; CD137 antigen; CD4 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Drb1 protein; Enzyme-linked immunosorbent assay; Experimental design; Female; Histocompatibility antigen HLA; HLA-DRB1 Chains - immunology; Humans; Immune system; Immunogenicity; Immunotherapy, Adoptive - methods; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - transplantation; Melanoma; Metastases; Metastasis; Middle Aged; Mutation; Patients; Peptides; Recombination; Regression analysis; T cell receptors; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - immunology; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - therapy; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor-infiltrating lymphocytes; Whole Exome Sequencing; γ-Interferon
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1423

The administration of autologous tumor-infiltrating lymphocytes (TILs) can mediate durable tumor regressions in patients with melanoma likely based on the recognition of immunogenic somatic mutations expressed by the cancer. There are limited data regarding the immunogenicity of mutations in breast cancer. We sought to identify immunogenic nonsynonymous mutations in a patient with triple-negative breast cancer (TNBC) to identify and isolate mutation-reactive TILs for possible use in adoptive cell transfer. A TNBC metastasis was resected for TIL generation and whole-exome sequencing. Tandem minigenes or long 25-mer peptides encoding selected mutations were electroporated or pulsed onto autologous antigen-presenting cells, and reactivity of TIL was screened by upregulation of CD137 and IFNγ ELISPOT. The nature of the T-cell response against a unique nonsynonymous mutation was characterized. We identified 72 nonsynonymous mutations from the tumor of a patient with TNBC. CD4 and HLA-DRB1*1501-restricted TILs isolated from this tumor recognized a single mutation in (recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples. Breast cancers can express naturally processed and presented unique nonsynonymous mutations that are recognized by a patient's immune system. TILs recognizing these immunogenic mutations can be isolated from a patient's tumor, suggesting that adoptive cell transfer of mutation-reactive TILs could be a viable treatment option for patients with breast cancer. .