Cetuximab-Activated Natural Killer and Dendritic Cells Collaborate to Trigger Tumor Antigen-Specific T-cell Immunity in Head and Neck Cancer Patients

被引:262
作者
Srivastava, Raghvendra M. [1 ]
Lee, Steve C. [1 ]
Andrade Filho, Pedro A. [1 ]
Lord, Christopher A. [1 ]
Jie, Hyun-Bae [1 ]
Davidson, H. Carter [1 ]
Lopez-Albaitero, Andres [1 ]
Gibson, Sandra P. [1 ]
Gooding, William E. [5 ]
Ferrone, Soldano [2 ,3 ,4 ,6 ]
Ferris, Robert L. [1 ,4 ,6 ]
机构
[1] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA
[4] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15260 USA
[5] Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA 15260 USA
[6] Univ Pittsburgh, Inst Canc, Canc Immunol Program, Pittsburgh, PA 15260 USA
关键词
FC-GAMMA-RIIIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; C-RECEPTOR POLYMORPHISMS; NON-HODGKINS-LYMPHOMA; BREAST-CANCER; CONCURRENT RADIOTHERAPY; PREDICT RESPONSE; EGFR EXPRESSION; NK CELLS; ANTIBODY;
D O I
10.1158/1078-0432.CCR-12-2426
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Purpose: Tumor antigen-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fc gamma receptor (Fc gamma R)-mediated cytotoxicity. However, the role of CD8(+) CTL and Fc gamma R in initiating innate and adaptive immune responses in mAb-treated human patients with cancer is still emerging. Experimental Design: Fc gamma RIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated patients with head and neck cancer (HNC). Flow cytometry was carried out to quantify EGF receptor (EGFR)-specific T cells in cetuximab-treated patients with HNC. The effect of cetuximab on natural killer (NK) cell, dendritic cell (DC), and T-cell activation was measured using IFN-gamma release assays and flow cytometry. Results: Fc gamma RIIIa polymorphism did not predict clinical outcome in cetuximab-treated patients with HNC; however, elevated circulating EGFR(853-861)-specific CD8(+) T cells were found in cetuximab-treated patients with HNC (P < 0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR(+) tumor cells and FcgRIIIa on NK cells but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-gamma-dependent expression of DC maturation markers, antigen processing machinery components such as TAP-1/2 and T-helper cell (T(H)1) chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK cell-induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another tumor antigen, MAGE-3. Conclusion: Cetuximab-activated NK cells promote DC maturation and CD8(+) T-cell priming, leading to tumor antigen spreading and T(H)1 cytokine release through "NK-DC cross-talk." Fc gamma RIIIa polymorphism did not predict clinical response to cetuximab but was necessary for NK-DC interaction and mAb-induced cross-presentation. EGFR-specific T cells in cetuximab-treated patients with HNC may contribute to clinical response. Clin Cancer Res; 19(7); 1858-72. (C)2013 AACR.
引用
收藏
页码:1858 / 1872
页数:15
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