Understanding the Low Immunogenicity of Basal Cell Carcinoma and Its Underlying Mechanisms

Basal cell carcinoma (BCC) is the most common form of skin cancer, characterized by its low responsiveness to immune-based therapies despite having the highest mutational burden among cancers. Recent research highlights that the immune system’s inability to effectively recognize and attack BCCs is primarily due to suppressed antigen presentation mechanisms originating from the tumor's cell of origin.

A key factor involves the loss of human leukocyte antigen class I (HLA-I) components, crucial for presenting tumor antigens to CD8+ T cells. This loss is especially prevalent in immune-excluded tumors, where immune cells are present but fail to infiltrate the tumor mass. The tumor cells in BCCs have been found to express the Foxc1 protein, which suppresses the expression of HLA-I, limiting antigen presentation.

Senior author Dr. Shawn Demehri and his team at Massachusetts General Hospital and Harvard Medical School conducted a comprehensive study comparing primary BCCs with squamous cell carcinomas (SCCs), which are more responsive to immunotherapy. Their findings revealed that even at early stages, BCCs exhibit an immune-excluded phenotype with minimal HLA-I expression. This suppression is driven by a stem-like, quiescent program inherited from the cell of origin, which epigenetically inhibits the antigen processing and presentation machinery (APM).

Importantly, the research identified Foxc1 as a critical regulator that downregulates IRF1 and HLA-I via epigenomic mechanisms. Reversing this suppression using drugs like entinostat, a histone deacetylase inhibitor, can restore antigen presentation in BCC cells, thereby potentially enhancing the effectiveness of immunotherapy.

Clinically, combining topical entinostat with immunotherapy agents such as imiquimod showed promising results by boosting antigen presentation and activating immune responses to eliminate BCC cells. These findings suggest that targeted epigenomic modulation may be a key strategy to overcome the immune-excluded phenotype of BCC and improve treatment outcomes.

This research emphasizes the importance of the tumor's cell of origin in determining immunogenicity and opens new avenues for developing combination therapies to treat BCC more effectively. As the incidence of keratinocyte carcinomas continues to rise, understanding and manipulating their immune evasion mechanisms could lead to more successful interventions.

Source: https://medicalxpress.com/news/2025-04-basal-cell-carcinoma-immunogenicity-linked.html