Immunotherapy for the Treatment of Cutaneous Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Boutros A
PROVIDER: S-EPMC8427439 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Although initial surgical excision cures 95% of patients, a minority of cutaneous squamous cell carcinomas (cSCCs) are judged to be unresectable, either locally advanced or with unresectable regional lymph nodes or distant metastases. These patients are offered systemic treatments. Response rate to chemotherapy is relatively low and not durable, as well as the results obtained with epidermal growth factor inhibitors (EGFRi). Like other cutaneous tumors, cSCCs have high immunogenicity, driven by the high mutational burden, the ultraviolet signature, and the overexpressed tumor antigens. Two checkpoint inhibitors, cemiplimab and pembrolizumab, achieved high response rate and survival with fewer toxicities than other available systemic agents. These promising results prompted to investigate new combination strategies of systemic therapy and surgery or radiotherapy. Subgroup analysis showed promising role of immunotherapy to facilitate surgery in locally advanced cSCC and, in a small group of patients, long-term survivals without resection. However, some cSCCs treated with immunotherapy develop either early or late resistance, so new drugs and new combinations are in a clinical study to overcome the mechanism underpinning these resistances. The present review focuses on the progress with immunotherapy to date and on new therapeutic strategies for cSCC.
| S-EPMC8766667 | biostudies-literature
Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.
| S-EPMC7962464 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) approaches have changed the therapeutic landscape for many tumor types. However, half of cutaneous squamous cell carcinoma (cSCC) patients remain unresponsive or develop resistance. Here, we show that, during cSCC progression in male mice, cancer cells acquire epithelial/mesenchymal plasticity and change their immune checkpoint (IC) ligand profile according to their features, dictating the IC pathways involved in immune evasion. Epithelial cancer cells, through the PD-1/PD-L1 pathway, and mesenchymal cancer cells, through the CTLA-4/CD80 and TIGIT/CD155 pathways, differentially block antitumor immune responses and determine the response to ICB therapies. Accordingly, the anti-PD-L1/TIGIT combination is the most effective strategy for blocking the growth of cSCCs that contain both epithelial and mesenchymal cancer cells. The expression of E-cadherin/Vimentin/CD80/CD155 proteins in cSCC, HNSCC and melanoma patient samples predicts response to anti-PD-1/PD-L1 therapy. Collectively, our findings indicate that the selection of ICB therapies should take into account the epithelial/mesenchymal features of cancer cells.
| S-EPMC11196727 | biostudies-literature
Project description:Background Cutaneous squamous cell carcinoma (CSCC) of the head and neck can require complex and disfiguring surgery in order to achieve cure, which can be morbid and negatively impact patient quality of life. The management of advanced CSCC has been revolutionized by immunotherapy with current clinical trials also exploring its role in the neoadjuvant and adjuvant settings. Patients may decline morbid curative surgery, such as orbital exenteration, and the outcomes of immunotherapy use in this unique group of patients require further investigation. Methods We reviewed the records of 119 patients treated at a major Australian quaternary oncology centre with immunotherapy (either cemiplimab or pembrolizumab) for advanced CSCC. Results We identified 7 patients recommended curative surgery involving orbital exenteration after multidisciplinary discussion, who declined surgery due to concerns about morbidity and/or disfigurement. All 7 patients demonstrated a response to treatment, and six avoided orbital exenteration. Two patients experienced pseudoprogression. Conclusions The management of CSCC can be complex and requires the input of a multidisciplinary team. Immunotherapy to avoid or reduce the extent of morbid definitive surgery is an emerging treatment option.
| S-EPMC8804342 | biostudies-literature
Project description:Non-melanoma skin cancers are one of the most common cancers diagnosed worldwide, with the highest incidence in Australia and New Zealand. Systemic treatment of locally advanced and metastatic cutaneous squamous cell carcinomas has been revolutionized by immune checkpoint inhibition with PD-1 blockade. We highlight treatment issues distinct to the management of the disease including expansion of the traditional concept of pseudoprogression and describe delayed responses after immune-specific response criteria confirmed progressive disease with and without clinical deterioration. We term this phenomenon "delayed response after confirmed progression (DR)". We also discuss the common development of second primary tumors, heterogeneous disease responses, and expanding clinical boundaries for immunotherapy use.
| S-EPMC8081898 | biostudies-literature
Project description:Hyperactive retrovirus-associated DNA sequence (Ras) genes have been found in human cancers and are involved in cancer pathogenesis. Salirasib, one anti-Ras compound, was reported to exhibit antitumoral effects, but its role remains unclear in cutaneous squamous cell carcinoma (cSCC). In our study, salirasib treatment led to deregulation of c-Raf, ERK and Akt signaling, blockage of MTOR signaling, interruption on Beclin 1-related autophagy regulation, activation of apoptosis and down-regulation of some cell cycle regulatory proteins in primary human epidermal keratinocyte (HEK)s, but did not exhibit similar effects in the human cSCC cell line COLO-16. MEK inhibitor U0126 can lead to dephosphorylation of MTOR and Rictor in COLO-16 cells; however, c-Raf was not yet down-regulated after salirasib treatment in the presence of U0126. Furthermore, we verified that the Ras activity could be suppressed by salirasib, and there was no loss-of-function mutation in c-Raf in HEKs and COLO-16 cells. In summary, salirasib does not exhibit antitumoral effects in the cSCC cells in assays in vitro. We speculated that the disability of signaling transmission from Ras to c-Raf in COLO-16 cells might contribute to the ineffective performance of salirasib.
| S-EPMC6160676 | biostudies-other
Project description:For most cutaneous basal cell and squamous cell carcinomas (nonmelanoma skin cancers (NMSCs)), data are insufficient to permit evidence-based choices among treatments. To compare tumor recurrence after treatments, we conducted a prospective cohort study of consecutive patients with primary NMSCs treated with the most common treatments, in two practices in 1999-2000. Recurrence was determined from medical records by observers blinded to treatment type. Follow-up was available for 1,174 patients with 1,488 tumors (93.8%) at median 7.4 years; of these tumors, 24.3% (N=361) were treated with destruction with electrodessication/curettage, 38.3% (N=571) with excision, and 37.4% (N=556) with histologically guided serial excision (Mohs surgery). The overall 5-year tumor recurrence rate (95% confidence interval) was 3.3% (2.3, 4.4). Unadjusted recurrence rates did not differ after treatments: 4.9% (2.3, 7.4) after destruction, 3.5% (1.8, 5.2) after excision, and 2.1% (0.6, 3.5) after Mohs surgery (P=0.26), and no difference was seen after adjustment for risk factors. In tumors treated only with excision or Mohs surgery, the hazard of recurrence was not significantly different, even after adjustment for propensity for treatment with Mohs surgery. These data indicate that common treatments for NMSCs were at least 95% effective, and further studies are needed to guide therapeutic choices for different clinical subgroups.
| S-EPMC3711403 | biostudies-literature
Project description:Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.
| S-EPMC6678994 | biostudies-literature
Project description:A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs.We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined significantly mutated, deleted, and amplified genes and associated genomic alterations with clinical variables.The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with human papillomavirus. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC, including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin.We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.
| S-EPMC4359951 | biostudies-other
Project description:Cutaneous squamous cell carcinoma (CSCC) is the second most common skin malignancy in white-skinned populations. Only a minority of patients (<5%) develop advanced disease, but this is often difficult to treat and characterised by a poor prognosis. Cemiplimab, a fully human IgG4 monoclonal antibody against programmed cell death-1 receptor, is indicated for advanced (i.e. locally advanced or metastatic) CSCC. Although the definition of metastatic CSCC is clear, there is currently no agreed definition of locally advanced CSCC. In recent guidelines, locally advanced CSCC was described as non-metastatic CSCC that is unlikely to be cured with surgery, radiotherapy or combination treatment. A multi-disciplinary advisory group of Italian CSCC experts was convened to develop criteria to assist in identifying appropriate candidates for cemiplimab therapy in advanced CSCC, based on the literature and clinical experience. In locally advanced CSCC, absolute, or mandatory, criteria for the use of cemiplimab are deep invasion, multiple lesions without defined margins, inadequate surgical excision margins and multiple recurrences, whereas relative criteria include large lesions, in critical or functionally significant areas and that are surgically complex. In addition, physicians should consider patient willingness/preferences (an absolute criterion), and their age and health status/comorbidities (relative criteria). It is hoped that these proposed absolute and relative criteria will help guide rational identification of patients who will receive maximum benefit from immunotherapy, while more clinical data accumulate.
| S-EPMC8753075 | biostudies-literature