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.

Review of the Tumor Microenvironment in Basal and Squamous Cell Carcinoma

“…However, for advanced or metastatic non-resectable cancers, management has transitioned to an immunotherapeutic approach [56]. The treatment of advanced BCC focuses on Shh inhibition, while therapy for SCC interferes with the PD-1/PD-L1 checkpoint [57,58].…”

“…For patients with SCC, surgical excision is the treatment modality of choice; however, for patients with increased risks of local recurrence, perineural spread, and metastasis, immunotherapy with cemiplimab, pembrolizumab, or nivolumab have been considered [55,58]. These drugs are PD-1 inhibitors, which inhibit the PD-1/PD-L1 immune checkpoint that typically decreases T cell functionality in the TME, suppresses the immune system, and accelerates cancer cell proliferation [58,60]. Therefore, treatment with these immunotherapy agents increases the volume of cytotoxic CD8+ T cells in the TME, allowing for tumor cell destruction [58].…”

“…These drugs are PD-1 inhibitors, which inhibit the PD-1/PD-L1 immune checkpoint that typically decreases T cell functionality in the TME, suppresses the immune system, and accelerates cancer cell proliferation [58,60]. Therefore, treatment with these immunotherapy agents increases the volume of cytotoxic CD8+ T cells in the TME, allowing for tumor cell destruction [58]. In advanced-stage patients who responded to neoadjuvant cemiplimab, the drug had an overwhelming response, with many patients achieving complete pathologic responses [61].…”

Comparison of Efficacy and Safety of First-Line Chemoimmunotherapy in Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Network Meta-Analysis

“…Existing evidence has suggested that ESCC should be viewed as a specifc disease that is extremely diferent from EAC clinically and biologically [2,4]. Recent studies even found that with a high burden of tumor mutation, massive infltration of infammatory cells, and increased expression of immunosuppression, ESCC seems to be associated with a favorable tumor microenvironment that could have a good response to ICIs [43]. Terefore, it was necessary to investigate the efciency and toxicity of frst-line chemoimmunotherapy in ESCC which also aligned with the principles of precision medicine.…”

Topical Immunotherapy for Actinic Keratosis and Field Cancerization

“…In this way, anti-PD-1 and PDL-1 inhibitors are used as immunotherapy for cancers with very good results [ 105 ]. Monoclonal antibodies against PD-1 have been tested in clinical trials for SCC including cemiplimab for the treatment of advanced cutaneous SCC and pembrolizumab for recurrent/metastatic cutaneous SCC [ 106 ]. It has been observed that T cells, Langerhans cells, and the expression of PDL-1 gradually increase during the progression from AK to in situ and invasive SCC, justifying the potential efficacy of their treatment with anti-PD-1/PDL1 immunotherapy [ 107 ].…”