Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer

DATTA J; BERK E; XU S; FITZPATRICK E; ROSEMBLIT C ; LOWENFELD L; GOODMAN N; LEWIS DA; ZHANG PJ; FISHER C; ROSES RE; DEMICHELE A; CZERNIECKI BJ

Breast Cacner Research

Springer

Lugar: New York; Año: 2015 vol. 17

PURPOSE: Lossof anti-HER2 CD4+ T-helper type-1 (Th1) immune response is observedin HER2pos-invasive breast cancer (IBC) patients compared to healthycontrols. Pathologic complete response (pCR) following neoadjuvanttrastuzumab/chemotherapy (T/C) portends an improved prognosis. We examineddifferences in anti-HER2 Th1 responses between pCR and <pCR patients toidentify modifiable immune correlates to pathologic response.  METHODS: Th1 responseswere examined using PBMCs pulsed with 6 HER2-class II peptides via IFN-γ ELISPOT.Th1 response metrics were responsivity,number of reactive peptides (repertoire),and cumulative response across 6 peptides(SFC/106 cells). Th1 responses of <pCR patients (n=4) receivingadjuvant HER2-pulsed type-1-polarized dendritic cell (DC1) vaccination wereanalyzed pre-/post-immunization.  RESULTS:Depressed anti-HER2 Th1 responses in treatment-naïve HER2pos-IBC patients(n=22) did not improve globally after T/C treatment (n=65). Compared withadjuvant-T/C, neoadjuvant-T/C (61.5%) was associated with higher Th1 repertoire(1.5 vs. 0.8, p=0.048). While pCR (n=16) and <pCR (n=24) patients did notdiffer in demographic/clinical characteristics, pCR patients were more likelyto have ERneg tumors. pCR patients demonstrated dramatically higher anti-HER2responsivity (94% vs. 33%, p=0.0002), repertoire (3.3 vs. 0.3, p<0.0001),and cumulative response (148.2 vs. 22.4, p<0.0001) versus <pCR patients.This disparity was mediated by CD4+T-bet+IFN-γ+phenotypes, and not attributable to <pCR patients? immune incompetence, host-levelT-cell anergy, or increased immunosuppressive populations. In recruited <pCRpatients, Th1 repertoire (3.7 vs. 0.5, p=0.014) and cumulative responses (192.3vs. 33.9, p=0.014) improved following HER2-pulsed DC1 vaccination.