Search Results (191)

The Kindlin family of scaffold proteins plays key roles in integrin-mediated processes. Kindlin-1 and -2, encoded by the FERMT1 and FERMT2 genes, respectively, are expressed in the epidermis. Kindlin-1 plays protective roles against the development of cutaneous squamous cell carcinomas (cSCCs) in epidermal keratinocytes. However, the role of Kindlin-2 in transformed epidermal keratinocytes has remained virtually unexplored. In this study, we used siRNA approaches to generate Kindlin-2-depleted cells in three isogenic transformed keratinocyte lines. PM1, MET1, and MET4 cells model, respectively, a precancerous lesion, a primary cSCC, and a metastatic lesion of the latter. MET1 cells express both Kindlin-1 and -2. However, Kindlin-1 was not detectable in PM1 and MET4 cells. FERMT2 silencing in PM1 and MET4, but not in MET1 cells, reduced proliferation and the ability to adhere to culture surfaces and spreading. Furthermore, Kindlin-2-depleted PM1 and MET4, but not MET1 cells, exhibited decreased numbers of focal adhesions, as well as an altered F-actin and microtubule cytoskeletal organization. Significantly, FERMT2 silencing reduced the directional migration in all three cell types. These findings are consistent with the concept that, in the absence of other Kindlin orthologues, Kindlin-2 plays a prominent role in the modulation of the proliferation, spreading, focal adhesion assembly, and motility of transformed keratinocytes, as exemplified by PM1 and MET4 cells. Full article

Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune–tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies. Full article

Background: Long non-coding RNAs (lncRNAs) are increasingly recognized as pivotal regulators in both inflammatory and neoplastic skin disorders. Their implications in numerous biological processes, including gene expression, immune responses, and epidermal homeostasis, suggest potential applications as diagnostic and prognostic markers, as well as therapeutic targets. Methods: We conducted a literature search on lncRNAs involved in both psoriasis and cutaneous squamous cell carcinoma (cSCC), highlighting overlapping pathogenic mechanisms. Results: Several lncRNAs, such as HOTAIR, MALAT-1, H19, and uc.291, display dysregulated expression in both psoriasis and cSCC, influencing keratinocyte proliferation and apoptosis, immune modulation, cytokine signaling, and the synthesis of epidermal proteins. Conclusions: The intersection of lncRNA function in chronic inflammation and skin carcinogenesis underscores their role in mediating the transition from psoriatic inflammation to tumorigenesis, offering new insights into disease susceptibility; further investigation through functional studies and clinical validation are required. The study of lncRNA-mediated molecular pathways is particularly relevant given the increased risk of non-melanoma skin cancers and lymphoproliferative disorders among patients with chronic and severe forms of psoriasis. Full article

Background/Objectives: Tumor-immune system interactions shape the progression of cutaneous squamous cell carcinoma (cSCC). Serum biomarkers for risk stratification remain limited. Complement factor H (CFH) regulates the alternative complement pathway. It has been linked to immunosuppression and cSCC development in tissue-based studies. We investigated whether serum CFH is associated with tumor aggressiveness and may help predict immunotherapy outcomes in advanced cSCC. Methods: In this retrospective, single-center study, pre-treatment serum CFH levels were measured in 104 cSCC patients (62 high-risk and 42 advanced) using ELISA. Associations with clinical characteristics, disease stage, and response to cemiplimab were analyzed. Subgroup comparisons considered immune status and inflammatory comorbidities. Results: Advanced cSCC patients had significantly higher CFH levels than high-risk patients (OR 0.13, p = 0.026), independent of tumor diameter or invasion depth. Among advanced cSCC cases, lower baseline CFH was associated with more prolonged progression-free survival (median 19.8 vs. 3.07 months, p = 0.029; HR 0.29, p = 0.014), independent of covariates including immunosuppression. CFH levels during therapy did not predict treatment response. ROC analysis showed moderate discriminatory ability with CFH alone (AUC 0.625), which improved when combined with clinical variables in a multivariable risk model (AUC 0.767). Conclusions: Serum CFH is an independent predictor of cemiplimab response and reflects biological aggressiveness in cSCC beyond conventional high-risk features. These findings support the use of CFH in clinical risk models and warrant external validation in multicenter cohorts. Full article

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC. Full article

Background: Actinic keratoses (AKs) are common pre-neoplastic lesions that may progress to cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) is an effective field-directed treatment for AK, but its impact on key biomarkers remains unclear. This study evaluates the clinical, dermatoscopic, and immunohistochemical effects of PDT on AK, with a focus on proliferation (Ki67, p53) and inflammation (COX-2) markers, to assess its efficacy in delaying carcinogenesis. Methods: In our prospective one-center study, we enrolled 31 patients with AK, with no history of previous AK treatment. They underwent three PDT sessions at four-week intervals, with follow-up eight weeks after the final session. Clinical, dermatoscopic, and immunohistochemical analyses of Ki67, p53, and COX-2 expression were performed before and after treatment. Results: Clinically, 54.8% of patients achieved complete lesion clearance, with no residual severe AK lesions. Ki67 and p53 immunoexpression significantly decreased post-PDT (p < 0.05), confirming its antiproliferative effect. COX-2 expression also declined significantly (p < 0.05), supporting PDT’s anti-inflammatory role. However, COX-2 remained stable or increased in 35.48% of cases, possibly due to inflammation-induced regeneration. There is a positive correlation between the reduction in Ki67, p53, and COX-2 immunoexpression and the decrease in AK severity (both according to Olsen grade and dermatoscopic grade). Conclusions: PDT effectively reduces AK severity, proliferation, and inflammation markers, potentially delaying carcinogenesis. However, residual biomarker expression suggests that additional treatment sessions or combination therapies may be necessary for complete lesion clearance. Further studies are required to optimize PDT protocols. Full article

The aim of this study was to develop a baseline [¹⁸F]FDG PET/CT model to predict immunotherapy response in advanced cutaneous squamous cell carcinoma (cSCC) and noninvasively determine tumor grade, thereby enhancing early patient stratification. We retrospectively analyzed 59 patients with histologically confirmed advanced cSCC submitted to immunotherapy with cemiplimab. All underwent [¹⁸F]FDG PET/CT at baseline and after approximately 12 weeks. Clinical response was assessed through PET findings integrated with clinical and dermatological evaluation, and patients were classified as responders (complete/partial metabolic response or stable disease) or non-responders (progression or toxicity-related discontinuation). Tumors were also classified as low to intermediate (G1–G2) or poorly differentiated (G3). Machine learning models (Random Forest and Extreme Gradient Boosting) were trained to predict treatment response and tumor grade. Clinical benefit was observed in 46/59 patients (77.9%), while 13 (22.1%) were non-responders. Histology showed 64.4% (n = 38) G1–G2 and 35.6% (n = 21) G3 tumors. The PET-based model best predicted clinical benefit (AUC = 0.96, accuracy = 91% cross-validation; AUC = 0.88, accuracy = 82% internal validation). For tumor grade prediction, the CT-based model achieved a higher AUC of 0.80 (accuracy 73%), whereas the PET-based model reached an AUC of 0.78 but demonstrated a slightly higher accuracy of 77%. Radiomic analysis of baseline [¹⁸F]FDG PET enables the discriminative prediction of immunotherapy response and tumor grade in advanced cSCC, with PET-based models outperforming CT-based ones. Full article

Background: A previous published Phase 2 trial using 2–4 doses of neoadjuvant cemiplimab in stage II–IV resectable cutaneous squamous cell carcinoma (CSCC) demonstrated that a complete pathological (pCR) rate of 51% and major pathological response (mPR) rate of 13% could be achieved with durable disease control. Methods: In this open-label, single-institution phase II trial (NCT05878288), patients with stage II–IV resectable CSCC received up to four doses of neoadjuvant cemiplimab prior to surgery. The primary endpoint of the study was to perform comprehensive molecular profiling. The focus of this report are the secondary clinical endpoints of pCR rate, mPR (defined as <10% viable tumour) rate, overall response rate (ORR) using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, immune-modified RECIST (imRECIST) and Immune PET Response Criteria in Solid Tumours (iPERCIST), disease-free survival (DFS), overall survival (OS), safety, and to describe changes in planned surgery. Results: Eleven patients were enrolled, with all proceeding with surgery. An ORR and pCR rate of 73% (8/11; 95% CI 0.39–0.93) was achieved, whilst 3/11 patients progressed on treatment. On pre-operative imaging, all 8/11 pCR patients demonstrated a partial response (RECIST 1.1), whilst 6/8 achieved a complete metabolic response and 2/8 a partial metabolic response (iPERCIST). Median follow-up was 10.2 (IQR 6.7–16.4) months. DFS was 91% (95% CI 0.57–1) and OS was 100% (95% CI 0.68–1), with one non-responder patient who developed recurrent locoregional and distant metastatic disease. There were no unexpected safety signals. Pathological features of response to neoadjuvant immunotherapy most commonly were granulomatous inflammation with keratin, fibrosis and inflammation. No cases with a dense inflammatory infiltrate were observed. Neoadjuvant immunotherapy did not impact the intra-operative planning and execution of surgery, but in the eight pCR cases, it reduced the extent of required surgery, whilst in the three non-responder cases, surgery was more extensive than originally planned. Conclusions: The DISCERN trial confirms that an excellent complete response rate can be achieved with four doses of neoadjuvant immunotherapy in stage II–IV CSCC. Proposed refinements to the pathological assessment of response and metabolic response criteria in CSCC for the neoadjuvant context are provided. Full article

The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management. Full article

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1^flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with diverse clinical presentations. This study aims to correlate findings from dermoscopy, ultrasonography, ex vivo confocal microscopy, and histology to improve diagnostic accuracy and guide better clinical management of cSCC. Methods: This cross-sectional study, conducted between July 2022 and December 2024, included 26 patients with 35 clinically suspicious cSCC tumors, analyzed through clinical, dermoscopic, high-frequency ultrasound (HFUS), ex vivo confocal fluorescence microscopy (FCM), and histopathology. Tumors were evaluated for various clinical, imaging, and histopathological criteria, such as tumor thickness, vascularization, differentiation degree, and invasion level, with FCM applied to 24 tumors for advanced microscopic analysis. Results: The study analyzed 35 cases of histopathologically confirmed cSCC, finding that invasive SCC was associated with greater tumor thickness, increased vascularization, and ulceration on both ultrasound and dermatoscopy, while in situ SCC showed homogeneous echogenicity and specific dermoscopic patterns like dotted vessels and white halos. Strong correlations were identified between ultrasound and histopathological measurements of tumor thickness and invasion depth, and confocal microscopy revealed that features like plump bright cells and nest-like structures were linked to invasive and poorly differentiated tumors. Conclusions: This study uniquely integrates advanced imaging techniques—dermatoscopy, skin ultrasound, and ex vivo confocal microscopy—with histopathological analysis to provide new insights into tumor grade, vascularity, and invasion depth in cSCC, enhancing non-invasive diagnosis. Full article

Cutaneous squamous cell carcinoma (CSCC) is one of the most common non-melanoma skin cancers, and particularly challenging to treat in advanced or metastatic stages. Traditional therapies, including chemotherapy and radiation, often result in limited efficacy and severe side effects. Cosibelimab, a fully human monoclonal antibody targeting PD-L1, has emerged as a promising immunotherapy for advanced CSCC. In this review, we evaluate the therapeutic potential of cosibelimab by analyzing its mechanism of action, clinical trial data, and its role compared to other PD-1/PD-L1 inhibitors, such as pembrolizumab and cemiplimab. We synthesized the available preclinical and clinical data on cosibelimab, focusing on published Phase I and II trial results involving 76 patients. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS), and safety profiles were compared between cosibelimab, pembrolizumab, and cemiplimab. Mechanistic insights into cosibelimab’s dual action, including PD-L1 blockade and antibody-dependent cellular cytotoxicity (ADCC), were also explored. Phase II trials demonstrated an ORR of 47.5%, with a median PFS of 12.9 months in advanced CSCC patients. Cosibelimab demonstrated a favorable safety profile, with predominantly mild to moderate adverse events. Comparative analysis with pembrolizumab and cemiplimab showed similar efficacy, although long-term survival data for cosibelimab is still emerging. Given its efficacy and safety, cosibelimab holds promise not only as a monotherapy but also for future exploration in combination regimens and broader oncologic indications. Future trials are required to validate its long-term outcomes, including overall survival, and to explore its use in combination therapies and neoadjuvant/adjuvant settings. Full article

The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing, with UV radiation being the main cause. Other risk factors are age, sex, skin type and immunosuppression. Human papillomaviruses (HPVs) are associated with benign and malignant skin tumours. In contrast to anogenital and oropharyngeal carcinomas, which are caused by alpha papillomaviruses, the HPV types associated with cSCC belong to the beta-HPV genus. These viruses infect the skin epithelium and are widespread in skin samples from healthy people. It is assumed that HPV amplifies the DNA damage caused by UV radiation and disrupts the repair mechanisms of the cells, without remaining permanently detectable in the tumour tissue, the so-called hit-and-run theory. The HPV status of tumours appears to have a positive influence on prognosis and response to therapy due to increased immune infiltration, in particular by tissue-resident memory T cells and activation of immune effector cells. This favours responses to immunotherapies such as PD-1/PD-L1 inhibitors, whereas immunosuppression may promote a pro-carcinogenic effect. In conclusion, the role of beta HPV in the development of cSCC appears to be closely associated with the immune status of the host. Depending on the immune status, beta HPV can play either a protective or a tumour-promoting role, and in view of the increasing incidence of skin cancer worldwide, enhancing the immune response against virus-infected keratinocytes, e.g., through HPV vaccination, could represent a promising approach for the prevention and therapy of squamous cell carcinomas. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) harbors one of the most mutated genomes. There are limited data on the genomic profile and its predictive potential for response to immunotherapy with PD-1 inhibitors in cSCC. Methods: This study retrospectively reviewed cSCC patients treated with PD-1 inhibitor monotherapy at a single institution. Clinical characteristics, treatment outcomes, PD-L1 expression, tumor mutation burden (TMB), and genomic profile in tumor and blood were analyzed. Logistic regression and a support vector classifier were used to validate identified biomarkers of significance. Results: Twenty-five patients were evaluable for response and had genomics tested in tumor and/or blood. Of the total, 80% of patients achieved an objective response: 40% complete response (CR), 32% partial response (PR) for more than 6 months, and 8% stable disease (SD) for more than 1 year; 20% of patients progressed on treatment. With a median follow-up of 21 months, progression-free survival (PFS) was 28 months in responders vs. 3 months in non-responders (p = 0.00001). Median PD-L1 was 25% in responders vs. 10% in non-responders (p = 0.39). There was no difference in median TMB between responders and non-responders. Eight gene mutations were significantly more frequent in non-responders than in responders: CDK12 (p = 0.005), CTCF (p = 0.033), CTNNB1 (p = 0.033), IGF1R (p = 0.038), IKBKE (p = 0.016), MLH1 (0.033), QKI (p = 0.016), and TIPARP (p = 0.033). A support vector model of these genes classified responders and non-responders with an accuracy of 0.88 in the training data and 1.0 in the testing data. Conclusions: PD-1 inhibitor monotherapy produces an impressive response. Eight gene mutations were significantly more frequent in non-responders. PD-L1 and TMB were inconclusive in predicting treatment response to anti-PD-L1. Full article

Background: Organ transplant recipients are at a significantly higher risk of developing skin cancer compared to the general population, particularly cutaneous squamous cell carcinoma. Approximately 3–8% of these carcinomas are located on the scalp. Scalp reconstruction is particularly challenging, especially for large excisions, due to the thickness of the scalp, the inelastic aponeurosis of the galea, and the integrity of the hair-bearing scalp. Additionally, in organ transplant recipients, the presence of numerous comorbidities and the increased risk of infection due to immunosuppressive therapy make management more complex. Based on our experience and the existing literature, we aim to describe possible reconstruction methods and discuss the combined management of medical and immunosuppressive therapy. Method: We present our experience with seven kidney transplant patients who underwent excision of cutaneous squamous cell carcinoma with a diameter larger than 3 cm. The crane technique involves three key steps. First, the tumor is excised with wide margins of disease-free tissue. Next, a pericranial flap is rotated and positioned to cover the exposed cranial bone. Finally, a bilayer dermal substitute is applied to create a microenvironment that supports skin graft implantation. Results: The crane technique was used for six patients. In one case, an O-Z rotation flap was used. All patients modified their immunosuppressive therapy, with those receiving antiproliferative therapy switching everolimus after surgery. Conclusions: When combined with a post-operative modification of the immunosuppressive regimen, the crane technique could be considered a feasible, safe, and effective approach to managing large cSCC of the scalp in fragile patients. Full article