Survivin-specific CD4+ T cells are decreased in patients with survivin-positive myeloma

Abstract

BackgroundSurvivin is a small protein inhibitor of apoptosis and a tumor associated antigen. Survivin expression in multiple myeloma is associated with poor prognosis, disease progression, and drug resistance. The CD4+ response against survivin remains uncharacterized.MethodsIn order to better understand the anti-tumor immune response to survivin, and optimize vaccination strategies, we characterized the spontaneous CD4+CD25- T cell response against survivin in healthy donors and myeloma patients using survivin derived peptide pools.ResultsHealthy donors and myeloma patients’ CD4+CD25- T cells exhibited a proliferative and IFN-gamma response against survivin peptides loaded onto autologous dendritic cells. We employed limiting dilution analysis to quantify the precursor frequency of survivin reactive CD4+CD25- T cells. Multiple myeloma patients (range 0% to 2.2x10-3%, n=12) had fewer survivin reactive CD4+CD25- T cells than healthy blood donors (range 1.1x10-3 to 8.4x10-3%, n=10), p = 0.021. The survivin reactive CD4+CD25- T cell precursor frequency was inversely associated with tumor survivin mRNA expression (p = 0.0028, r = −1.0, n = 6), and survivin tumor protein expression by IHC (p = 0.0295, r = −0.67, n = 10). A full length mutant survivin protein-pulsed dendritic cell vaccine expanded survivin reactive CD4+CD25- T cells after 12 days of in vitro culture (range 0-540x,median = 42x), and expansion was achieved even in patients with low baseline survivin reactive CD4+ precursors.ConclusionsWe have, for the first time, quantified the circulating CD4+CD25- precursor frequency against survivin and demonstrated this is lower in myeloma patients than healthy donors. The number of survivin reactive CD4+CD25- T cells is inversely associated with tumor survivin expression suggesting suppression of survivin responsive CD4+CD25- T cells. Further exploration of a full length mutant survivin protein vaccine which expands survivin reactive CD4+ cells independent of the survivin reactive precursor frequency is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0065-1) contains supplementary material, which is available to authorized users.

Inhibition of Human Dendritic Cell ER Stress Response Reduces T Cell Alloreactivity Yet Spares Donor Anti-tumor Immunity

“…DMSO (0.1%) or B-I09 (20 μM) was added once on day 0 of the culture. T cell proliferation was determined after 3 days of culture (34).…”

Chromatin binding of survivin regulates glucose metabolism in the IFN-γ producing CD4+T cells

“…In autoimmune conditions, survivin has been attracting attention in a variety of diseases including autoimmune arthritis (24), psoriasis (25), and MS (26). Targeting survivin in experimental and clinical autoimmunity was efficient in reducing inflammation, proliferation, and tissue damage (27)(28)(29)(30)(31), while its role in cell metabolism has never been assessed.…”

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF‐κB activation in the Barrett metaplasia–dysplasia–adenocarcinoma sequence

“…) in various cancers such as myeloma (Locke et al . ), lung cancer (Li & Ding ) and ovarian cancer (Berinstein et al . ).…”

“…Survivin is an anti-apoptotic, NF-jBinducible gene (Kawakami et al 2005;Wang et al 2010). It is involved in the control of proliferation and apoptosis in T-cell development (Xing et al 2004) in various cancers such as myeloma (Locke et al 2015), lung cancer (Li & Ding 2015) and ovarian cancer (Berinstein et al 2015).…”