Immunotherapy for the Treatment of Squamous Cell Carcinoma: Potential Benefits and Challenges

Abstract

Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime.

Keywords: immunotherapy; nonmelanoma skin cancers (NMSCs); risk factors of SCC; squamous cell carcinoma (SCC).

Figure 1

Commonly mutated genes associated with the risk factors of SCC. UVR, ultraviolet radiation; OTRs, organ transplant recipients; TERT, telomerase reverse transcriptase; ROS, reactive oxygen species; MAPK; mitogen-activated protein kinase; FOXM1; forkhead box M1; COX2, Cyclooxygenase 2; MMPs; matrix metalloproteinases, HPV, human papillomavirus; CDKN2A; cyclin-dependent kinase inhibitor 2A; FAT1, FAT atypical cadherin 1.

Figure 2

Immunogenic characteristics of SCC that favor the benefits observed in immunotherapy treatment for SCC patients. The tumor microenvironment (TME) of the SCC patients is characterized by high tumor mutational burden (TMB), increased infiltration with tumor associated macrophages (TAMs) and lymphocytes, and increased PD-L1 expression, which work as a favorable prognostic factor for immunotherapy in SCC patients.

Figure 3

Challenges usually occur in the immunotherapy treatment in SCC patients. Patients with high TMB and advanced or metastatic stage get more benefit from immunotherapy. Expression of PD-L1, immune cells, and TAMs are useful as biomarkers. IFN-γ causes immunotherapy resistance through PD-L1-dependent or -independent pathways and by producing adenosine deaminase acting on RNA 1 and yes-associated protein. TMB, tumor mutational burden; PD-L1, programmed cell death-ligand 1; TAMs, tumor-associated macrophages.