Tumor Immune Profiling to Optimize Clinical Trial Readiness in Basal Cell Nevus Syndrome

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SUMMARY Germline mutations in PTCH underlie basal cell nevus syndrome (BCNS), a dominantly inherited disorder also known as Gorlin-Goltz syndrome, in which affected individuals manifest accelerated Hh signaling, leading to inordinate tumor burden that requires multiple, costly and often mutilating surgical procedures. Moreover, BCNS patients develop multiple BCCs in sun-protected areas illustrating their unique tumor susceptibility. Except for tumor-intrinsic Hh signaling, mechanisms underpinning the spontaneous growth and development of BCCs remain unclear. Our group has fostered bench-to-bedside clinical trials with targeted agents in these patients, ultimately leading to FDA approval of the SMO inhibitor (SMOi) vismodegib for treatment of advanced BCCs. Despite substantial anti-tumor efficacy, a major challenge with SMOi has been the emergence of clinical resistance and significant tumor recurrence, as well as intolerable side-effects causing half or more patients to discontinue treatment. Additional preclinical and clinical studies from our group and others clearly indicate that Hh signaling inhibition alone may be necessary but insufficient to permanently eradicate BCCs. This indicates a need to develop novel treatment strategies to ameliorate the limitations of current SMOi’s to improve treatment outcomes. Utilizing our genetically engineered Ptch1+/-/SKH-1 mouse model that faithfully recapitulates the pathogenesis of human BCNS BCCs, we have demonstrated that (i) Hh signaling promotes accumulation of FoxP3+ cells and increases pro-tumorigenic cytokines and chemokines in Ptch1-deficient skin; (ii) SMO inhibition increases CD8+ cells and CXCL10/11, chemokines involved in T cell recruitment; and (iii) treatment of BCC- bearing Ptch1+/-/SKH-1 with anti-PD-1 results in significant tumor regression. These data, together with recent reports showing efficacy of immune checkpoint inhibitors (anti-CTLA4 or anti-PD-1) in human BCCs, strongly support the role of immune mechanisms in BCC growth, and underscore the potential utility of combined SMO and immune checkpoint blockade to reduce tumor burden. To facilitate a future multi-center, single-arm trial of combined therapy of vismodegib and nivolumab (humanized monoclonal anti-PD-1 antibody) in BCNS patients, this application aims to define tumor immune correlates relevant to BCNS microenvironments in Ptch1+/-/SKH-1 mice. In Aim 1, we will characterize immune cell populations and determine the immunologic mechanisms relevant to Hh signaling, and in Aim 2, we will comprehensively define tumor immune profiles and elucidate immunologic correlates predictive of anti-tumor responses to vismodegib and PD-1 blockade.