Depicting the Immunological Landscape of Basal Cell Carcinoma Subtypes

BACKGROUND: Anti-PD-1 response has been associated with higher PD-1 ligand (PD-L1) expression levels in different cancer types. Cemiplimab, an anti-PD-1 antibody, has been shown to induce a response rate of 31% and 22% in patients with locally advanced basal cell carcinoma (BCC) and metastatic BCC respectively, who have progressed or are intolerant to Hedgehog Inhibitors (HHi). The lower-than-expected efficacy of anti-PD-1 antibodies and limited and conflicting data on PD-L1 expression in BCC have prompted us to characterize the prerequisites for immune response-PD-L1, dendritic cells (DCs), and HLA expression with immunohistochemistry in different BCC morphological subtypes, namely superficial, nodular, sclerosing/infiltrative, and basosquamous. METHODS: In this retrospective study, a total of 77 tumor samples from 4 BCC subtypes were analyzed by immunohistochemistry. Among the BCC subtypes, we assessed PD-L1 and CD11c + DCs expression within tumor and stroma, and HLA Class I expression in the tumor compared to the epidermis. Non-automated quantification of positive tumor cells and peri- and intratumoral immune cells was performed by a board-certified pathologist. RESULTS: In all BCC subtypes, tumor cells (SOX9 positive) were negative for PD-L1. PD-L1 was expressed on intra- and peritumoral immune cells, predominantly in basosquamous BCCs, where 80% of the samples showed PD-L1 positivity in immune cells. DCs were predominantly found in the peritumoral area, mostly in basosquamous BCC, whereas superficial BCCs showed the least DCs. HLA class I expression was downregulated compared to epidermis in most specimens without significant differences among the subtypes. CONCLUSION: Our findings support previous reports on the immune-privileged status of BCC. Contrary to the literature, we could not confirm PD-L1 expression on BCC cells, but rather on the intra- and peritumoral immune cells. Given these results and the literature suggesting a tendency of higher immunoreactivity compared to other BCC subtypes, basosquamous BCC might be a better target for anti-PD-1 therapy as opposed to other subtypes.