Factors in the tumor microenvironment promote immunosuppression that permits tumor escape from immune destruction. Our data show that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumor inflammatory lymphocyte (TIL) infiltrate. PD-L1 is widely expressed in many tumors and is the target of two successful new cancer immunotherapy approaches, but is a poor predictor of treatment efficacy. We define novel effects of tumor intrinsic PD-L1 signaling on tumor proliferation, cancer stem cell properties, in vivo growth independent of anti-tumor immunity, and regulation of mTOR signals and autophagy. We extend the concept of adaptive immune resistance by studying how tumor intrinsic PD-L1 alters anti-tumor immunity in vastly greater depth and detail than current studies that solely focus on the capacity of tumor PD-L1 to kill anti- tumor T cells. Despite the known role for PD-L1 in immunosuppression and the promising clinical benefits of ?PD-L1 therapy, there remain significant gaps in understanding the role of tumor PD-L1 in the ?PD-L1 response, immune modification, and tumorigenic potential through tumor intrinsic signaling. Our proposed studies will address these gaps by employing mouse models for ovarian cancers and melanoma cells that are PD-L1+ and engineered versions that are PD-L1lo or PD-L1-, and novel models of heterogeneous tumor PD-L1 expression to test our overarching hypothesis that anti-tumor immunity and response to ?PD-L1 therapy are directed by tumor-intrinsic PD-L1 signals. We will address this hypothesis with the following specific aims:
Specific Aim 1 : Test the hypothesis that anti-tumor immunity and response to ?PD-L1 therapy are modulated by heterogeneous tumor PD-L1 expression. We study mouse models for ovarian and melanoma tumors that are PD-L1+ and engineered versions that are PD-L1lo, PD-L1KO or PD-L1hi. We will employ B16 melanoma and ID8 ovarian cancer, along with PD-L1 KO mice, to define the mechanism of ?PD-L1 therapy on anti-tumor TIL quantity and function, and determine which aspects of anti-tumor immunity are responsible for treatment effects of ?PD-L1 in PD-L1lo/neg tumors. We will also define immune cell trafficking and T regulatory suppression effects altered by heterogeneous tumor PD-L1 expression with ?PD-L1 therapy Specific Aim 2: Test the hypothesis that tumor PD-L1 regulation of tumor intrinsic mTOR and autophagy affects anti-tumor immunity and clinical outcomes. We will focus on control of tumor mTOR and autophagy (which are likely related) based on preliminary data, determining immune consequences by evaluating downstream effector molecules (e.g., CCL2, CCL9, CXCL12) using blocking antibodies and genetic interventions, and evaluate the impact on anti-tumor immunity in vivo. We will determine PD-L1 signals in stem cell development using validated in vitro and in vivo assays whether these properties are the result of PD-L1 regulation of tumor intrinsic signaling through mTOR and autophagy.
Factors defining the tumor immune cell infiltrates that drive progression and alter immunotherapy effects are largely unknown. We identified tumor intrinsic PD-L1 (B7-H1, CD274) as a major regulator of these infiltrates with profound effects on tumor progression, and response to immunotherapy. As many tumor types express PD-L1, which is also a target of successful immunotherapies, our studies have very broad potential applications and could lead to field-changing insights and paradigms.
|Clark, Curtis A; Gupta, Harshita B; Curiel, Tyler J (2017) Tumor cell-intrinsic CD274/PD-L1: A novel metabolic balancing act with clinical potential. Autophagy 13:987-988|
|Clark, Curtis A; Gupta, Harshita B; Sareddy, Gangadhara et al. (2016) Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. Cancer Res 76:6964-6974|