CD4+ T-Helper Type 1 Cytokines and Trastuzumab Facilitate CD8+ T-cell Targeting of HER2/neu-Expressing Cancers

DATTA J; XU S; ROSEMBLIT C; SMITH JB; CINTOLO JA; POWELL DJ JR; CZERNIECKI BJ

cancer immunology research

American Association for Cancer Research

Lugar: Philadelphia; Año: 2015 vol. 3

2326-6074

Vaccination strategiesincorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2369-377) areincreasingly utilized in HLA-A2pos HER2/neu-expressing cancer patients. The failure of post-vaccinationHER2369-377-specific CD8+ T-cells to recognize HLA-A2posHER2/neu-expressing cells in vitro, however, has been attributedto the impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcilethis controversy by demonstrating that HER2369-377 is directlyrecognized by high functional-avidity HER2369-377-specific CD8+T-cells ? either genetically modified to express a novel HER2369-377T-cell receptor or sensitized using HER2369-377-pulsed type 1-polarizeddendritic cells ? on class I-abundant HER2low, but not class I-deficientHER2high, cancer cells invitro. Importantly, we demonstrate a critical cooperation between CD4+T-helper type 1 (Th1) cytokines IFN-γ/TNF-α and HER2-targeted antibodytrastuzumab in restoring surface class I expression, thereby facilitating HER2369-377-specificCD8+ T-cell recognition and lysis of HER2/neu-expressing cancer cells. Although activation of EGFR and HER3 signalingsignificantly abrogated IFN-γ/TNF-α and trastuzumab-induced class Irestoration, EGFR/HER3 receptor blockade rescued class I expression in HER2/neu-expressing cells. Thus, combinationsof CD4+ Th1 immune interventions and multivalent targeting of HERfamily members may be required for optimal anti-HER2/neu CD8+ T-cell-directed immunotherapy.