title: Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.
abstract: BACKGROUND
  A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.
  
  
  METHODS
  Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.
  
  
  RESULTS
  Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.
  
  
  CONCLUSIONS
  Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Jashodeep.datta@uphs.upenn.edu.
authors.forename: Jashodeep
authors.initials: J
authors.lastname: Datta
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. erik.berk@uphs.upenn.edu.
authors.forename: Erik
authors.initials: E
authors.lastname: Berk
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. wenleiwa@mail.med.upenn.edu.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Elizabeth.fitzpatrick@uphs.upenn.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. cinthia.rosemblit@uphs.upenn.edu.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Rosemblit
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. lea.lowenfeld@uphs.upenn.edu.
authors.forename: Lea
authors.initials: L
authors.lastname: Lowenfeld
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. noah.goodman@uphs.upenn.edu.
authors.forename: Noah
authors.initials: N
authors.lastname: Goodman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. david.lewis2@uphs.upenn.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. paul.zhang2@uphs.upenn.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Carla.fisher@uphs.upenn.edu.
authors.forename: Carla
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Robert.roses@uphs.upenn.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Roses
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. angela.demichele@uphs.upenn.edu.|Department of Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. angela.demichele@uphs.upenn.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. brian.czerniecki@uphs.upenn.edu.|Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. brian.czerniecki@uphs.upenn.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014611:Vaccination; D055815:Young Adult
chemical_list: D019496:Cancer Vaccines; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases