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

Cancer Immunology Research
Jashodeep DattaBrian J Czerniecki

Abstract

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-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 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 HER2(low), but not class I-deficient HER2(high), 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 HER2(high) 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...Continue Reading

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Citations

Jun 18, 2015·Frontiers in Immunology·Jashodeep DattaBrian J Czerniecki
Feb 7, 2018·Disease Markers·Martina Di ModicaTiziana Triulzi
Jan 10, 2020·Archivum Immunologiae Et Therapiae Experimentalis·Atefeh ArabJavad Behravan
May 2, 2018·Oncoimmunology·Lea LowenfeldBrian J Czerniecki
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Dec 19, 2020·Cancer Cell·Giulia PetroniLorenzo Galluzzi
May 21, 2021·Frontiers in Immunology·Amrita BasuKrithika Kodumudi
Aug 28, 2021·Journal of Personalized Medicine·Anna BurguinFrancine Durocher

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