Novel immunotherapies for cancer are having a major clinical impact, in particular anti-PD-1 mAbs. However, the mechanisms that explain why a subset of patients responds to these therapies while other patients do not remain incompletely understood. Our preliminary data suggest that a baseline T cell-inflamed tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies. Combination immunotherapies may push clinical efficacy in this subset of patients further. Our over-arching hypothesis is that germline polymorphisms in the host, genomic features of the tumor cells, and the composition of intestinal microbiota profoundly influence the extent of a spontaneous T cell response against a patient's tumor, which in turn will determine the likelihood of response to immunotherapy. Identifying molecular mechanisms for T cell exclusion should point towards new therapeutic interventions that will expand the fraction of patients responding to anti-PD-1- based immunotherapies. While our work to date has focused on melanoma, recent TCGA analysis has indicated that many of the same principles apply to multiple additional cancer types. Thus, a major goal of the proposed funding period will be to broaden our translational research strategy to encompass patients with all cancer types being treated with anti-PD-1- based immunotherapies. The output of this work is therefore anticipated to have profound impact on cancer patient outcomes overall.
The overall purpose of this proposal is to identify new strategies for cancer immunotherapy based on understanding the molecular features of the T cell-inflamed and non-T cell-inflamed tumor microenvironment. Our overall approach relies on a reverse-translational strategy of analyzing multiple dimensions of genomic data with respect to clinical outcome with anti-PD-1 treatment.
|Hantel, Andrew; Gabster, Brooke; Cheng, Jason X et al. (2018) Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab. J Immunother Cancer 6:73|
|Matson, Vyara; Fessler, Jessica; Bao, Riyue et al. (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:104-108|
|Horton, Brendan L; Williams, Jason B; Cabanov, Alexandra et al. (2018) Intratumoral CD8+ T-cell Apoptosis Is a Major Component of T-cell Dysfunction and Impedes Antitumor Immunity. Cancer Immunol Res 6:14-24|
|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|
|Fessler, Jessica L; Gajewski, Thomas F (2017) The Microbiota: A New Variable Impacting Cancer Treatment Outcomes. Clin Cancer Res 23:3229-3231|