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

Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2(369-377)) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2(369-377)-specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2(369-377) is directly recognized by high functional-avidity HER2(369-377)-specific CD8(+) T cells-either genetically modified to express a novel HER2(369-377) TCR or sensitized using HER2(369-377)-pulsed type 1-polarized dendritic cells (DC1)-on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T-helper type-1 (Th1) cytokines IFN gamma/TNF alpha and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2(369-377)-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neuexpressing cells by IFN gamma/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2(369-377)-CD8(+) T-cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFN gamma/TNF alpha and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2(369-377)-CD+ cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8(+) T-cell-directed immunotherapy.