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

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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. RESULTS: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 TNF? 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 TNF? or IL17, but not IFN?, 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. CONCLUSIONS: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.

SUBMITTER: Phan-Lai V

PROVIDER: S-EPMC4854769 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Phan-Lai Vy V Dang Yushe Y Gad Ekram E Childs Jennifer J Disis Mary L ML

Clinical cancer research : an official journal of the American Association for Cancer Research 20151209 9

<h4>Purpose</h4>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.<h4>Experimental design</h4>Using the TgMMTV-neu murine mammary tumor model, we cultured T cells derived from mice immunized with a previ ...[more]

PMID: 26660518

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Project description:OBJECTIVE:Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies. METHODS:We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies. RESULTS:We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (F(ST) = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (P(meta) = 3.61 x 10(-6)), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (P(meta) = 3.48 x 10(-12)), type 1 DM (P(meta) = 5.33 x 10(-5)), and CD (P(meta) = 5.30 x 10(-3)). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; P(meta) = 2.61 x 10(-25), odds ratio 0.73 [95% confidence interval 0.69-0.78]). CONCLUSION:Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

Dataset Information

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

Publications

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

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