The long-term focus of my research has been to understand the cellular and molecular signals that promote the generation of potent and long-lasting tumor-specific T cell responses. We have incorporated Toll-like receptor (TLR) agonists into vaccines containing peptides or proteins, representing defined tumor antigens (TA). These vaccines augment the generation of tumor-specific T cells and enhances antitumor responses in a prophylactic and therapeutic setting of prostate cancer and melanoma (in mice). WE also documented that the administration of TLR ligands into mice leads to the accumulation of CD4 and CD8 T cells in vivo. This occurs in part by preventing T cell death that normally takes place as a mechanism to maintain T cell homeostasis in vivo. Throughout the course of these studies, we attributed the enhanced T cell responses to the stimulation of TLRs on professional antigen presenting cells (APC). However, recent data have led us to question the role that direct TLR engagement on tumor-specific CD8 T cells has on potentiating T cell activation and augmenting antitumor responses.
We recently demonstrated that activated CD4 and CD8 T cells express certain TLRs and the engagement of these receptor enhanced T cell responses. For example, we reported that TLR2 engagement directly on CD8 T cells decreased the activation threshold. This resulted in the increased production of effector molecules IFN-y, perforin, granzyme B and Fas ligand. The increased production of these molecules correlated with enhanced cytolytic activity against a melanoma tumor that expressed the immunodominant epitope derived from chicken ovalbumin protein. Additionally, we demonstrated that TLR9 engagement on CD4 T cells in vivo and in vitro increased cell survival in part by augmenting the expression levels of anti-apoptotic molecules. Through these studies, we have gained a greater understanding of how TLR agonists potentiate antitumor T cell responses. We are currently studying the molecular pathway by which TLR stimulation on tumor-specific T cells potentiates effector responses and examining the therapeutic efficacy of treating tumor-bearing hosts with T cells engineered to overexpress TLRs or to express certain TLR ligands.
Degui Geng, Liqin Zheng, Ratika Srivastava, Cruz Velasco-Gonzalez, Adam Riker, Svetomir N. Markovic, Eduardo Davila. Enhancing tumor immunogenicity by amplifying TLR-MyD88 signals in tumor-specific CD8 T cells. (Received favorable comment; Under revision; 2010; Cancer Research)
Geng D, Zheng L, Asprodites N, Velasco-Gonzalez C, Davila E. When Toll-like receptor and TCR signals collide: A mechanism of costimulation. (Received favorable comment; Under revision; 2010; Blood)
Asprodites N, Zheng L, Geng D, Velasco-Gonzalez C, Sanchez-Perez L, Davila E. Engagement of toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and this interaction augments anti-tumor activity. PMID: 18587008. FASEB J 2008; 22: 3628-3637.
Zheng L, Asprodites N, Keene AH, Rodriguez P, Brown KD, Davila E. TLR9 engagement on CD4 T lymphocytes represses gamma-radiatioin-induced apoptosis through activation of checkpoint kinase response elements. PMID: 18086870 Blood. 2008 Mar 1; 111(5): 2704-13.
Byrne GW, Stalboerger PG, Davila E, Heppelmann CJ, Gazi MH, McGregor HCJ, LaBreche PT, Davies WR, Rao VP, Oi K, Tazelaar HD, Logan JS, McGregor CGA. Proteomic identification of non-Gal antibody targets after pig-to-primate cardiac xenotransplantation. PMID: 18957049. Xenotransplantation 2008; 15: 268-276.