Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade

Abstract

Monoclonal antibodies that block immune regulatory proteins such as programmed death-1 (PD-1) have demonstrated remarkable efficacy in controlling the growth of multiple tumor types. Unresectable or metastatic basal cell carcinoma, however, has largely gone untested. Because PD-Ligand-1 (PD-L1) expression in other tumor types has been associated with response to anti-PD-1, we investigated the expression of PD-L1 and its association with PD-1 expression in the basal cell carcinoma tumor microenvironment. Among 40 basal cell carcinoma specimens, 9/40 (22%) demonstrated PD-L1 expression on tumor cells, and 33/40 (82%) demonstrated PD-L1 expression on tumor-infiltrating lymphocytes and associated macrophages. PD-L1 was observed in close geographic association to PD-1+ tumor infiltrating lymphocytes. Additionally, we present, here, the first report of an objective anti-tumor response to pembrolizumab (anti-PD-1) in a patient with metastatic PD-L1 (+) basal cell carcinoma, whose disease had previously progressed through hedgehog pathway-directed therapy. The patient remains in a partial response 14 months after initiation of therapy. Taken together, our findings provide a rationale for testing anti-PD-1 therapy in patients with advanced basal cell carcinoma, either as initial treatment or after acquired resistance to hedgehog pathway inhibition.

Keywords: Anti-PD-1; Basal cell carcinoma; Hedgehog; PD-L1; Pembrolizumab.

Fig. 1

Geographic co-localization of PD-L1+ tumor cells and associated immune cells with PD-1+ infiltrating immune cells in BCC. PD-1, programmed death-1; PD-L1, programmed death ligand-1. 200× original magnification, all panels

Fig. 2

Partial response of metastatic basal cell carcinoma to pembrolizumab (anti-PD-1). Computed tomography (CT) scans performed pre-therapy (top row) and 6.5 months after initiating pembrolizumab (anti-PD-1, bottom row) demonstrate regression of basal cell carcinoma lung metastases. Yellow arrowheads indicate sites of metastases

Fig. 3

Immune elements in the microenvironment of a pre-treatment basal cell carcinoma from a patient who responded to anti-PD-1 therapy. The immune infiltrate abuts the tumor islands and is composed of a mixture of CD4 and CD8+ T-cells at a ratio of approximately 2:1. The CD8 cells are cytotoxic, as supported by the punctate cytoplasmic TIA-1 immunostaining. The lymphocytic infiltrate is accompanied by CD68+ macrophages. PD-1 is seen on approximately half of the lymphocytes present, and is immediately adjacent to PD-L1 expression in the tumor microenvironment, consistent with an immune microenvironment primed for potential response to PD-1/PD-L1 checkpoint blockade. PD-L1 is expressed predominantly on immune cells, rather than tumor cells in this example. H & E, hematoxylin and eosin, PD-(L)1, programmed death-(Ligand)1. 200× original magnification, all panels