PT  - JOURNAL ARTICLE
AU  - Datta, Jashodeep
AU  - Xu, Shuwen
AU  - Rosemblit, Cinthia
AU  - Smith, Jenessa B.
AU  - Cintolo, Jessica A.
AU  - Powell, Daniel J.
AU  - Czerniecki, Brian J.
TI  - CD4<sup>+</sup> T-Helper Type 1 Cytokines and Trastuzumab Facilitate CD8<sup>+</sup> T-cell Targeting of HER2/<em>neu</em>–Expressing Cancers
AID  - 10.1158/2326-6066.CIR-14-0208
DP  - 2015 May 01
TA  - Cancer Immunology Research
PG  - 455--463
VI  - 3
IP  - 5
4099  - http://cancerimmunolres.aacrjournals.org/content/3/5/455.short
4100  - http://cancerimmunolres.aacrjournals.org/content/3/5/455.full
SO  - Cancer Immunol Res2015 May 01; 3
AB  - Vaccination strategies incorporating the immunodominant HLA-A2–restricted HER2/neu-derived peptide 369–377 (HER2369–377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369–377-specific CD8+ T cells to recognize HLA-A2posHER2/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 HER2369–377 is directly recognized by high functional-avidity HER2369–377-specific CD8+ T cells—either genetically modified to express a novel HER2369–377 TCR or sensitized using HER2369–377-pulsed type 1–polarized dendritic cells (DC1)—on class I–abundant HER2low, but not class I–deficient HER2high, cancer cells. Importantly, a critical cooperation between CD4+ T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2high cancers, thereby facilitating recognition and lysis of these cells by HER2369–377-specific CD8+ T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369–377-CD8+ T-cell–mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369–377-CD8+ 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. Cancer Immunol Res; 3(5); 455–63. ©2015 AACR.