The focus of this research theme is to identify and characterize prevention-relevant tumor antigens, and to develop animal models for cancer immunoprevention strategies that are most likely to be translatable into applications for preventing cancer in individuals at higher risk for developing cancer.
- IRX-2, a natural cytokine biological with multiple components, has been used in preclinical and clinical studies to promote antitumor activity of T lymphocytes. To define cellular mechanisms responsible for antitumor effects of IRX-2, its ability to induce effector T cells (Teff) was examined in a model simulating the tumor microenvironment. In this in vitro model, IRX-2 promoted Teff expansion and antitumor activity without inducing Treg, and thus, IRX-2 could be considered as a promising component of future antitumor therapies. (Schilling et. al., J Mol Med (Berl). 2012 Feb;90(2):139-47).
- Cancer-initiating cells (CIC) are considered to represent the subpopulation of tumor cells that is resistant to conventional cancer treatments, highly tumorigenic in immunodeficient mice, and responsible for tumor recurrence and metastasis. Based on an elevated aldehyde dehydrogenase (ALDH) activity attributable to ALDH1/3 isoforms, ALDH(bright) cells have been identified and isolated from tumors and shown to have characteristics of CIC. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8(+) T cells. We found that adoptive therapy with ALDH1A1-specific CD8(+) T cells eliminated ALDH(bright) cells, inhibited tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice. These results strongly support the potential of ALDH1A1-based immunotherapy to selectively target CICs in human cancer. (Visus et. al., Clin Cancer Res. 2011 Oct 1;17(19):6174-84).
- Recent studies suggest that tumor cell-derived high mobility group box 1 (HMGB1) may suppress naturally acquired CD8 T cell-dependent antitumor immunity via enhancing Treg to produce IL-10, which is necessary for Treg-mediated immune suppression. (Liu et. al., J Immunol. 2011 Jul 1;187(1):118-25).
- NY-ESO-1 and LAGE-1 represent highly homologous cancer-germline antigens (Ags) frequently coexpressed by many human cancers, but not by normal tissues, except testis. In contrast to NY-ESO-1, little is known about spontaneous immune responses to LAGE-1. Collectively, our findings define the hierarchy of immunodominance of spontaneous LAGE-1-specific CD4(+) T cell responses in patients with advanced melanoma. These findings demonstrate the capability of LAGE-1 to stimulate integrated cellular and humoral immune responses that do not cross-react with NY-ESO-1. Therefore, they provide a strong rationale for the inclusion of LAGE-1 peptides or protein in vaccine trials for patients with NY-ESO-1(+)/LAGE-1(+) tumors. (Kudela et. al., J Immunol. 2011 Jan 1;186(1):312-22).