Overcoming Resistance to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma

SIMPLE SUMMARY: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans. The therapeutic landscape of CSCC has change in recent years, after the approval of immune checkpoint inhibitors (ICI) in advanced CSCC. However, not all patients will respond to ICI, and those who respond may develop resistance over time. Understanding the predictors of response to immunotherapy and the mechanisms underlying primary and acquired resistance to ICIs may help identify which patients could best benefit from these therapies. Many treatment strategies are under development to overcome resistance to immunotherapy, such as immune checkpoint inhibitors plus vaccines, oncolytic virus, radiotherapy, chemotherapy, or tumor microenvironment modulators. ABSTRACT: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC.