title: Characterization of an Immunogenic Mutation in a Patient with Metastatic Triple-Negative Breast Cancer.
abstract: Purpose: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.Experimental Design: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.Results: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 inRBPJ(recombination signal binding protein for immunoglobulin kappa J region). Analysis of 16 metastatic sites revealed that the mutation was ubiquitously present in all samples.Conclusions: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.Clin Cancer Res; 23(15); 4347-53. ©2017 AACR.
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.|George Washington University School of Medicine and Health Sciences, Washington, DC.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Assadipour
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Zacharakis
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.|Robert Wood Johnson Medical School, Newark, New Jersey.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Crystal
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Robert P T
authors.initials: RPT
authors.lastname: Somerville
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Black
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Harshini
authors.initials: H
authors.lastname: Chinnasamy
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Isaac
authors.initials: I
authors.lastname: Kriley
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Lily
authors.initials: L
authors.lastname: Lu
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Yong-Chen
authors.initials: YC
authors.lastname: Lu
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Goff
authors.affiliation: Surgery Branch, NCI, Bethesda, Maryland. feldmanst@mail.nih.gov.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D005260:Female; D059811:HLA-DRB1 Chains / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000637:transplantation; D008875:Middle Aged; D009154:Mutation; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D000073359:Exome Sequencing
chemical_list: D059811:HLA-DRB1 Chains; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9