Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Genetic activation of Hedgehog (HH)/GLI signaling causes basal cell carcinoma (BCC), a very frequent non-melanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) proved an efficient medical therapy of BCC, although lack of durable responses and frequent development of drug resistance pose major challenges to anti-HH treatments. In light of the recent breakthroughs in cancer immunotherapy, we analyzed in detail the possible immunosuppressive mechanisms in HH/GLI-induced BCC. 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 led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including PD-1/PD-L1. Anti-PD1 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 results provide a comprehensive survey of the immune status of murine BCC and provide 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 in vivo the efficacy of immunotherapeutic strategies.