Modulating the tumor microenvironment to induce cross priming for cancer immunotherapy
Erica L. Fleming-Trujillo1, Pablo Saenz-Lopez Larrocha2, Michael I. Nishimura2
Loyola University of Chicago, Maywood IL
1Department of Microbiology & Immunology, 2Department of Surgery
We, and others, have observed biologic and anti-tumor responses in both humans and mice following adoptive cell transfer (ACT) of T cells transduced to express T cell receptors (TCRs) specific for melanoma antigens. Limitations to this therapy include the monospecificity of transferred T cells and the immunosuppressive tumor microenvironment. We hypothesize that local injection of allogeneic transduced T cells has the potential to create a favorable, pro-inflammatory response that is conducive to recruitment and activation of host immune cells that can subsequently elicit a protective, systemic anti-tumor response. In order to improve upon this immunotherapy utilizing a mouse melanoma model, we propose to use intratumoral injection of HLA-A2 restricted, tyrosinase-specific T cells from an allogeneic (H-2d) donor into B16 tumors expressing HLA-A2, established in HLA-A2 (A2/H-2b) transgenic mice. We have shown in vitro that allogeneic, tyrosinase-specific T cells have increased lytic activity and pro-inflammatory cytokine production against B16 A2 tumors compared to syngeneic transduced T cells. In vivo, B16 A2 tumors injected with allogeneic, tyrosinase-specific T cells have a significant reduction in tumor growth compared to tumors injected with syngeneic transduced T cells or untransduced allogeneic T cells. Preliminary data suggests that treated mice mount T cell responses to additional H-2b restricted melanoma antigens, as measured by IFN-γ ELISPOT. We seek to investigate the mechanisms of improved anti-tumor immune responses by characterizing the immune cell infiltration into the tumor microenvironment and the impact on host dendritic cell and T cell activation. Allogeneic transduced T cells could provide an “off the shelf” therapy that physicians can perform in any clinical setting for any malignancy accessible by a needle, making this therapy available to more patients.