Immunotherapy is evolving to become established as a potent therapeutic modality for the treatment of multiple cancer types. Notably in melanoma, but also in other cancer entities including lung cancer, head and neck cancer and breast cancer, it has become increasingly apparent that a subset of tumors demonstrates the presence of tumor-reactive T cells present within the tumor microenvironment, while others lack such an infiltrate. The absence of an anti-tumor immune response within the tumor microenvironment recently has been correlated with the lack of responsiveness against immunotherapies, including anti-PD-1. Thus, identifying the molecular mechanisms causing the lack of T cell infiltration will be crucial for expanding the clinical efficacy of immunotherapies. Recent work from our laboratory has identified tumor-cell intrinsic Wnt/?- catenin signaling as a potential cause for the lack of an anti-tumor T cell infiltrate in malignant melanoma. Using patient material, we identified a correlation between lack of a T cell-gene signature and enhanced ?- catenin target genes. Using an inducible autochthonous mouse model, we showed that suppression of dendritic cell-attracting chemokines was directly mediated by ?-catenin signaling, resulting in a lack of tumor- infiltrating dendritic cells. The deficiency in dendritic cells was directly correlated with a lack of T cell activation and failed T cell recruitment. Based on these observations we hypothesize that tumor cell-intrinsic activation of specific oncogenic pathways determine the composition of the tumor microenvironment and directly impact the anti-tumor immune response. To test this hypothesis we propose: (1) to evaluate whether tumor-intrinsic ?-catenin activation mediates resistance to an expanded effector T cell population and adoptive T cell therapy; (2) to develop novel treatment strategies to generate a T cell-attracting tumor microenvironment; (3) to determine whether activation of additional oncogenic pathways can mediate immune exclusion from the tumor microenvironment; and (4) to interrogate if the activation of the Wnt/?-catenin pathway is associated with T cell exclusion in cancer types beyond melanoma. The proposed studies aim to elucidate key mechanistic event in tumor escape from host immunity, and therefore will provide highly important insights in the interplay between a growing tumor and the immune system. Furthermore, understanding the basic mechanisms will be the first step in achieving the overarching translational goal to reverse T cell exclusion in patients, thus expanding the fraction of patients showing clinical benefit to immunotherapeutic interventions.
The presence of CD8+ T cells within the tumor microenvironment has emerged as a potent biomarker to predict clinical response towards immunotherapeutic interventions. Recent work from our group has identified the first tumor-intrinsic mechanism (activated Wnt/?-catenin signaling) which directly mediates exclusion of CD8+ T cells from the tumor microenvironment. The aims of this proposal are to elucidate details of this ?-catenin- mediated exclusion-process, to interrogate whether other oncogenic pathways contribute to the exclusion of T cells in melanoma and other cancers, and to identify therapeutic solutions to overcome this barrier to effective immunotherapy.
|Spranger, Stefani; Dai, Daisy; Horton, Brendan et al. (2017) Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 31:711-723.e4|
|Peng, Weiyi; Chen, Jie Qing; Liu, Chengwen et al. (2016) Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16|
|Sweis, Randy F; Spranger, Stefani; Bao, Riyue et al. (2016) Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer. Cancer Immunol Res 4:563-8|
|Spranger, Stefani (2016) Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 28:383-91|
|Spranger, Stefani; Luke, Jason J; Bao, Riyue et al. (2016) Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc Natl Acad Sci U S A 113:E7759-E7768|