The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent

Infusion of HER2-specific T cells, derived from vaccine-primed patients and expanded with IL2/IL12, has induced tumor regression in a minority of patients with metastatic treatment-refractory HER2(+) breast cancer. We questioned whether alteration of cytokine growth factors used to culture vaccine-p...

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Bibliographic Details
Published in:Clinical cancer research 2016-05, Vol.22 (9), p.2207-2216
Main Authors: Phan-Lai, Vy, Dang, Yushe, Gad, Ekram, Childs, Jennifer, Disis, Mary L
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - immunology
Cancer Vaccines - immunology
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Cytokines - immunology
Female
Humans
Interleukin-17 - immunology
Interleukin-2 - immunology
Interleukins - immunology
Lymphocytes, Tumor-Infiltrating - immunology
Mammary Neoplasms, Experimental - immunology
Mice
Receptor, ErbB-2 - immunology
Tumor Necrosis Factor-alpha - immunology
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Summary:Infusion of HER2-specific T cells, derived from vaccine-primed patients and expanded with IL2/IL12, has induced tumor regression in a minority of patients with metastatic treatment-refractory HER2(+) breast cancer. We questioned whether alteration of cytokine growth factors used to culture vaccine-primed T cells could improve antitumor activity. Using the TgMMTV-neu murine mammary tumor model, we cultured T cells derived from mice immunized with a previously defined neu class II peptide, p98-114 (neu p98), and evaluated different cytokine combinations for expansion. Infusion of neu p98-specific T-cell lines derived from all cytokine conditions evaluated resulted in significant antitumor activity compared with infused naïve splenocytes (P < 0.05). T cells cultured with IL2/IL21 could uniquely mediate complete regression of spontaneous mammary tumors. IL2/IL21 cultured neu-specific T cells demonstrated a different cytokine secretion pattern as compared with other cultured T cells; secreting high levels of TNFα and IL17 (P < 0.05). Moreover, tumor-infiltrating CD8(+) cells were significantly increased after the infusion of IL2/IL21 cultured T cells as compared with tumors treated with T cells expanded under other cytokine conditions (P < 0.001). The antitumor effect of the infusion of IL2/IL21 cultured cells was mediated by CD8 T cells. Depletion of TNFα or IL17, but not IFNγ, abrogated the tumor growth inhibition induced by the IL2/IL21 T cells and markedly decreased the influx of CD8 into tumors. Finally, IL2/IL21-cultured human antigen specific T cells also displayed a similar polyfunctional Th1/Th17 phenotype. Expansion of HER2 vaccine-primed T cells with IL2/IL21 may have the potential to effectively mediate tumor regression when used in adoptive transfer. Clin Cancer Res; 22(9); 2207-16. ©2015 AACR.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-15-2273