PD-1 and beyond to Activate T Cells in Cutaneous Squamous Cell Cancers: The Case for 4-1BB and VISTA Antibodies in Combination Therapy

Simple Summary The use of checkpoint antibodies has revolutionized the treatment of cancer. Tumor-infiltrating T cells, key mediators of anti-tumor immune responses, are often actively silenced by the tumor microenvironment. Checkpoint antibodies block inhibitory signals or enhance positive signaling pathways in these T cells to overcome silencing, resulting in an improved anti-tumor T-cell response. To date, many clinical studies have focused on blocking inhibitory pathways (e.g., CTLA-4 and PD-1), with varying success. Increasingly, alternative checkpoint molecules are being identified and used as monotherapies, or in combination with existing PD-1/CTLA-4 treatments. This review dissects the potential role of checkpoint antibodies against PD-1, VISTA and 4-1BB in the future treatment of cutaneous skin cancers. Non-melanoma skin cancers (NMSC) have a higher incidence than all other cancers combined with cutaneous squamous cell carcinoma (cSCC), capable of metastasis, representing approximately 20% of NMSCs. Given the accessibility of the skin, surgery is frequently employed to treat localized disease, although certain localities, the delineation of clear margins, frequency and recurrence of tumors can make these cancers inoperable in a subset of patients. Other treatment modalities, including cryotherapy, are commonly used for individual lesions, with varying success. Immunotherapy, particularly with checkpoint antibodies, is increasingly a promising therapeutic approach in many cancers, offering the potential advantage of immune memory for protection against lesion recurrence. This review addresses a role for PD-1, 4-1BB and VISTA checkpoint antibodies as monotherapies, or in combination as a therapeutic treatment for both early and late-stage cSCC.