Progressive Loss of Anti-HER2 CD4+ T-helper Type 1 Response in Breast Tumorigenesis and the Potential for Immune Restoration

DATTA J; ROSEMBLIT C ; BERK E; SHOWALTER L; MICK R; LEE KP; ABBA M; YANG RL ; KELZ RR; FITZPATRICK E; HOYT C; FELDMAN MD; ZHANG PJ; XU S; KOSKI GK; CZERNIECKI BJ

Oncoimmunology

Landes Biosciences

Lugar: Austin, TX; Año: 2015

2162-4011

Genomic profiling has identified severalmolecular drivers in breast tumorigenesis. A thorough understanding of endogenousimmune responses to these drivers may provide insights into potential immuneinterventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4+Th1 responses across a continuum in HER2-driven breast tumorigenesis in order todetermine whether these responses are associated with tumor progression. Ahighly significant stepwise loss in Th1 response from healthy donors or patientswith benign breast disease, through HER2pos-DCIS, and ultimately to earlystage HER2pos-invasive breast cancer (IBC) was detected by ELISPOT.  This anti-HER2 Th1 deficit, specific toHER2-overexpressing tumors, was not attributable to lack of immune competenceor increased circulating immunosuppressive phenotypes (Treg or MDSCs),but resulted in a shift in IFN-γ/IL-10-producing phenotypes. Furthermore,IFN-γ/TNF-α receptor-expressing HER2pos BC cell lines were highlysusceptible to Th1 cytokine-mediated apoptosis. While unaffected by surgery,chemotherapy, or HER2-targeted therapy (trastuzumab), the depressed Th1responses in HER2pos-IBC patients were significantly restored byHER2-pulsed dendritic cell immunization, suggesting that this Th1 defect is not?fixed? and can be corrected with immunologic interventions. Finally, intact anti-HER2Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy,while significantly depressed Th1 responses were observed in patients incurringBC events following trastuzumab/chemotherapy. Thus, anti-HER2 Th1 immunity maybe explored as a biomarker for HER2-directed therapies. Moreover, combinationsof existing HER2-targeted therapies with therapies to boost anti-HER2 CD4+Th1 immunity warrant further investigation and may decrease the risk of BC recurrence.