Abstract
Genetic activation of hedgehog/glioma-associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti-HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI-induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)-1/PD-ligand 1. Anti-PD-1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies invivo.
Highlights
Basal cell carcinoma (BCC) of the skin represents a very common human cancer entity with around 3-4 million new cases diagnosed per year in the US alone (Sekulic and Von Hoff, 2016)
Single case and prove-of-concept studies have suggested that immunotherapeutic approaches can be successful (Chang et al, 2019, Lipson et al, 2017), very little is known about how oncogenic Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling regulates tumor immunity in basal cell carcinoma (BCC)
Given the exceptionally high mutational burden of human BCC (Bonilla et al, 2016), we here hypothesized that i) HH/GLI-induced BCC are immunogenic, ii) HH/GLI signaling establishes an immune-suppressive immune microenvironment and iii) HH/GLI-induced BCC are susceptible to immunotherapy
Summary
Basal cell carcinoma (BCC) of the skin represents a very common human cancer entity with around 3-4 million new cases diagnosed per year in the US alone (Sekulic and Von Hoff, 2016). Despite the striking therapeutic efficacy of SMO inhibitors, their successful clinical use is limited and challenged by frequent a priori and acquired drug resistance, lack of durable responses, severe adverse effects and relapse of patients upon drug withdrawal. These limitations call for novel therapeutic regimens improving the response rates and durability of the therapeutic effect of HH inhibitors (Atwood et al, 2013, Atwood et al, 2015, Sekulic and Von Hoff, 2016, Sharpe et al, 2015, Tang et al, 2012, Whitson et al, 2018)
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