The focus of this research theme is to understand the complex interactions between components of the immune system and tumors and their microenvironment, immunosuppression in tumor-bearing individuals, and escape of tumors from immunological control.
- Cytotoxic T cells that are present in tumors and capable of recognizing tumor epitopes are impotent in eliciting tumor rejection. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8(+) T-cell dysfunction may reveal effective strategies for immune therapy. The inhibitory receptors PD-1 and Tim-3 are known to negatively regulate CD8(+) T-cell responses directed against the well-characterized tumor antigen NY-ESO-1. It is shown that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1-specific CD8(+) T-cell expansion and function in melanoma. Therefore, targeting BTLA along with the PD-1 and Tim-3 pathways is critical to reverse an important mechanism of immune escape in patients with advanced melanoma (Fourcade et.al., Cancer Res. 2012 Feb 15;72(4):887-96).
- Dendritic cells (DCs) are the most potent antigen presenting cells (APCs). Whereas immature DCs down-regulate T-cell responses to induce/maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, because they repress target mRNAs of acceptor DCs. Our findings unveil a mechanism of transfer of exosome-shuttle miRNAs between DCs and its role as a means of communication and posttranscriptional regulation between DCs. (Montecalvo et. al., Blood. 2012 Jan 19;119(3):756-66).
- MUC1 is a transmembrane glycoprotein abnormally expressed in all stages of development of human adenocarcinomas. Overexpression and hypoglycosylation of MUC1 in cancer cells compared with normal epithelial cells are likely to alter its function and affect the behavior of cancer cells. The extracellular domain, specifically the highly O-glycosylated VNTR (variable number of tandem repeats) region, plays an important role in cell-cell communication; however, CIP members show that it also participates intracellularly in activation of the NF-κB pathway. This may be a novel mechanism that tumors can use to promote inflammation and cancer development (Cascio et.al., J Biol Chem. 2011; 286:42248-56).
- The immunogenic heat shock proteins (HSPs) gp96, hsp70 and calreticulin (CRT) bind to CD91 on antigen-presenting cells (APCs) for cross-presentation of the HSP-chaperoned peptides. This event leads to priming of T-cell responses. Here we show that CD91 serves as a signaling receptor for these HSPs, allowing for the maturation of APCs, secretion of cytokines and priming of T-helper (Th) cells. These results are important for development of T-cell responses in situ in tumor-bearing hosts and for vaccination against cancer and infectious disease. (Pawaria and Binder. Nat Commun. 2011 Nov 1;2:521).