Resistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature

BACKGROUND: Immunotherapy with immune checkpoint inhibitors has radically changed the management of a broad spectrum of tumors. In contrast, only very limited information is available about the efficacy of these therapies in non-melanoma skin cancers, especially in basal cell carcinoma. The latter malignancy is often associated with both an impairment of the host immune response and a high mutation burden, suggesting that immune checkpoint inhibitor-based immunotherapy may be effective in the treatment of this tumor. CASE PRESENTATION: A 78-year-old woman was diagnosed with a metastatic non-small-cell-lung-cancer. Following the lack of response to two lines of systemic chemotherapy, she was treated with the anti-PD-1 monoclonal antibody nivolumab, obtaining a prolonged stable disease. Under nivolumab treatment, the patient developed a basal cell carcinoma of the nose. The latter was surgically resected. Immunohistochemical staining of tumor tissue showed a PD-L1 expression < 1% and lack of human leukocyte antigen class I subunit (i.e. heavy and light chain) expression on tumor cells. In addition, a limited number of T cells (CD3+) was present in the tumor microenvironment, with a higher number of regulatory T cells (Foxp3+) and macrophages (Cd11b+) as compared to a low infiltration of activated cytotoxic T cells (CD8+/ Granzyme B+). Two months following the surgical removal of the tumor, while still on nivolumab treatment, the patient relapsed with a basal cell carcinoma in the same anatomic site of the previous surgical excision. The tumor displayed the same pathological characteristics. CONCLUSION: Preclinical lines of evidence suggest a potential role of immune checkpoint inhibitors for basal cell carcinoma treatment. However, limited clinical data is available. In the patient we have described administration of the immune checkpoint inhibitor nivolumab for the treatment of a responsive non-small cell carcinoma was associated with the development and relapse of a basal cell carcinoma tumor. This association is likely to reflect the resistance of basal cell carcinoma cells to anti-PD-1 based immunotherapy because of a "cold" tumor microenvironment characterized by lack of human leukocyte antigen class I expression, low PD-L1 expression and high number of immune regulatory cells.