Pathogenesis Of Non-melanoma Skin Cancer Research Articles

The Association of Vitamin D with Non-Melanoma Skin Cancer Risk: An Umbrella Review of Systematic Reviews and Meta-Analyses.

Background and Objectives: Previous studies revealed the anti-angiogenic, antiproliferative, and anti-inflammatory effects of Vitamin D (VitD) on cancer cells. Although this body of evidence supported the correlation of high VitD levels with reduced incidence rates for various malignancies, contradictory results were reported regarding non-melanoma skin cancer (NMSC). The aim of this overview was to summarize the available evidence from the existing pool of systematic reviews and meta-analyses, focusing on VitD serum status, dietary intake, and VitD receptor (VDR) polymorphisms in correlation to NMSC incidence. Materials and Methods: A literature search in electronic databases was conducted from inception to January 2023. The inclusion criteria were systematic reviews and meta-analyses published in peer-reviewed journals, evaluating VitD serum levels, dietary and/or supplementary intake, or VDR gene polymorphisms, and reporting data on NMSC. Results: A total of 10 studies were included in the data analysis models. A positive association between VitD serum levels and NMSC is highlighted. However, dietary/supplementation of VitD does not exhibit a likewise strong linkage to NMSC. Despite the contradictory findings, VDR polymorphisms may play a crucial role in the intricate NMSC pathogenesis. Conclusions: This umbrella review shows that high VitD levels are associated with increased NMSC incidence, potentially due to its direct correlation with increased sun exposure. Further research on VDR polymorphisms is suggested to explore their true effect size on NMSC risk.

Serine and one-carbon metabolism sustain non-melanoma skin cancer progression

Non-melanoma skin cancer (NMSC) is a tumor that arises from human keratinocytes, showing abnormal control of cell proliferation and aberrant stratification. Cutaneous basal cell carcinoma (cBCC) and cutaneous squamous cell carcinoma (cSCC) are the most common sub-types of NMSC. From a molecular point of view, we are still far from fully understanding the molecular mechanisms behind the onset and progression of NMSC and to unravel targetable vulnerabilities to leverage for their treatment, which is still essentially based on surgery. Under this assumption, it is still not elucidated how the central cellular metabolism, a potential therapeutical target, is involved in NMSC progression. Therefore, our work is based on the characterization of the serine anabolism/catabolism and/or one-carbon metabolism (OCM) role in NMSC pathogenesis. Expression and protein analysis of normal skin and NMSC samples show the alteration of the expression of two enzymes involved in the serine metabolism and OCM, the Serine Hydroxy-Methyl Transferase 2 (SHMT2) and Methylen-ThetraHydroFolate dehydrogenase/cyclohydrolase 2 (MTHFD2). Tissues analysis shows that these two enzymes are mainly expressed in the proliferative areas of cBCC and in the poorly differentiated areas of cSCC, suggesting their role in tumor proliferation maintenance. Moreover, in vitro silencing of SHMT2 and MTHFD2 impairs the proliferation of epidermoid cancer cell line. Taken together these data allow us to link the central cellular metabolism (serine and/or OCM) and NMSC proliferation and progression, offering the opportunity to modulate pharmacologically the involved enzymes activity against this type of human cancer.

Wnt Signaling Pathways: From Inflammation to Non-Melanoma Skin Cancers.

Canonical and non-canonical Wnt signaling pathways are involved in cell differentiation and homeostasis, but also in tumorigenesis. In fact, an exaggerated activation of Wnt signaling may promote tumor growth and invasion. We summarize the most intriguing evidence about the role of Wnt signaling in cutaneous carcinogenesis, in particular in the pathogenesis of non-melanoma skin cancer (NMSC). Wnt signaling is involved in several ways in the development of skin tumors: it may modulate the inflammatory tumor microenvironment, synergize with Sonic Hedgehog pathway in the onset of basal cell carcinoma, and contribute to the progression from precancerous to malignant lesions and promote the epithelial-mesenchymal transition in squamous cell carcinoma. Targeting Wnt pathways may represent an additional efficient approach in the management of patients with NMSC.

Neutrophil Gelatinase-Associated Lipocalin as Potential Predictive Biomarker of Melanoma and Non-Melanoma Skin Cancers in Psoriatic Patients: A Pilot Study.

Background: Studies have demonstrated a higher risk of nonmelanoma skin cancers (NMSC) and a modestly increased melanoma risk in patients with psoriasis. To date, no biomarkers predictive of evolution have been identified yet. Methods: The aim of this prospective case-control study was to investigate the potential role of neutrophil gelatinase-associated lipocalin (NGAL) as a predictive biomarker of skin cancers in psoriatic patients. Patients with a diagnosis of psoriasis were enrolled, as well as healthy subjects and patients with skin cancers as controls. Plasma protein expression of NGAL, metalloproteinases (MMP)-2, and MMP-9 was performed by an enzyme-linked immunosorbent assay (ELISA). In all the patients who developed skin cancer at follow-up, NGAL, MMP-2, and MMP-9 serum levels were dosed again. Results: Plasma NGAL levels were significantly higher in psoriatic patients with NMSC than without (182.3 ± 36.6 ng/mL vs. 139.9 ± 39.3 ng/mL) (p < 0.001). Plasma NGAL levels were significantly higher (p < 0.00001) in patients with psoriasis and NMSC than in patients with skin tumors without psoriasis (182.3 vs. 122.9). Patients with psoriasis who developed NMSC at follow-up showed increased plasma MMP-9 levels. Conclusion: NGAL seems to play a role in the pathogenesis of NMSC but not melanoma in patients with psoriasis.

170 Non-melanoma skin cancer and hereditary hemochromatosis: A retrospective cohort study

Hereditary hemochromatosis (HH) is a genetic disease of altered iron homeostasis. HH causes skin hyperpigmentation and various diseases, such as hepatocellular carcinoma via oxidative stress. Although oxidative damage also plays a role in the pathogenesis of non-melanoma skin cancer (NMSC), the link between HH and NMSC remains unknown. Data on HH patients with skin neoplasms and controls from 1980 to 2021 matched by age, sex, and race were extracted. HH carriers without disease and/or those without pathology-proven skin neoplasms were excluded.

Wounding Therapies for Prevention of Photocarcinogenesis.

The occurrence of non-melanoma skin cancer (NMSC) is closely linked with advanced age and ultraviolet-B (UVB) exposure. More specifically, the development of NMSC is linked to diminished insulin-like growth factor-1 (IGF-1) signaling from senescent dermal fibroblasts in geriatric skin. Consequently, keratinocyte IGF-1 receptor (IGF-1R) remains inactive, resulting in failure to induce appropriate protective responses including DNA repair and cell cycle checkpoint signaling. This allows UVB-induced DNA damage to proliferate unchecked, which increases the likelihood of malignant transformation. NMSC is estimated to occur in 3.3 million individuals annually. The rising incidence results in increased morbidity and significant healthcare costs, which necessitate identification of effective treatment modalities. In this review, we highlight the pathogenesis of NMSC and discuss the potential of novel preventative therapies. In particular, wounding therapies such as dermabrasion, microneedling, chemical peeling, and fractionated laser resurfacing have been shown to restore IGF-1/IGF-1R signaling in geriatric skin and suppress the propagation of UVB-damaged keratinocytes. This wounding response effectively rejuvenates geriatric skin and decreases the incidence of age-associated NMSC.

Immunohistochemical expression of SOX2 in non‐melanoma skin cancer

Basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC) are the most common non-melanoma skin cancer (NMSC). SOX2 is a transcription factor that acts on various phases of embryonic development and its overexpression in many tumors has been reported. This work aimed to evaluate the possible role of SOX2 in pathogenesis of non-melanoma skin cancer through its immunohistochemical assessment in BCC and SCC compared to normal skin and correlating its expression with the established prognostic factors. The investigated cases were 24 BCC, 21 SCC, and 26 normal skin specimens. SOX2 was not expressed in normal skin, but it was upregulated in SCC (85.7%) and BCC (66.7%), with a significant difference between malignant cases and normal skin (p<0.001). However, SOX2 expression did not differ between SCC and BCC. SOX2 expression was associated with large-sized tumors in all malignant cases (BCC plus SCC) (p=0.02) and in SCC (p=0.043) alone together with its liability to be expressed in advanced stage in SCC (p=0.063). SOX2 was over-expressed in cutaneous SCC and BCC without a significant difference. SOX2may enhance progression of NMSC manifested by its association with large tumor size and advanced stage.

Non-Melanoma Skin Cancer in People Living With HIV: From Epidemiology to Clinical Management.

Skin cancers represent the most common human tumors with a worldwide increasing incidence. They can be divided into melanoma and non-melanoma skin cancers (NMSCs). NMSCs include mainly squamous cell (SCC) and basal cell carcinoma (BCC) with the latest representing the 80% of the diagnosed NMSCs. The pathogenesis of NMSCs is clearly multifactorial. A growing body of literature underlies a crucial correlation between skin cancer, chronic inflammation and immunodeficiency. Intensity and duration of immunodeficiency plays an important role. In immunocompromised patients the incidence of more malignant forms or the development of multiple tumors seems to be higher than among immunocompetent patients. With regards to people living with HIV (PLWH), since the advent of combined antiretroviral therapy (cART), the incidence of non-AIDS-defining cancers (NADCs), such as NMSCs, have been increasing and now these neoplasms represent a leading cause of illness in this particular population. PLWH with NMSCs tend to be younger, to have a higher risk of local recurrence and to have an overall poorer outcome. NMSCs show an indolent clinical course if diagnosed and treated in an early stage. BCC rarely metastasizes, while SCC presents a 4% annual incidence of metastasis. Nevertheless, metastatic forms lead to poor patient outcome. NMSCs are often treated with full thickness treatments (surgical excision, Mohs micro-graphic surgery and radiotherapy) or superficial ablative techniques (such as cryotherapy, electrodesiccation and curettage). Advances in genetic landscape understanding of NMSCs have favored the establishment of novel therapeutic strategies. Concerning the therapeutic evaluation of PLWH, it’s mandatory to evaluate the risk of interactions between cART and other treatments, particularly antiblastic chemotherapy, targeted therapy and immunotherapy. Development of further treatment options for NMSCs in PLWH seems needed. We reviewed the literature after searching for clinical trials, case series, clinical cases and available databases in Embase and Pubmed. We review the incidence of NMSCs among PLWH, focusing our attention on any differences in clinicopathological features of BCC and SCC between PLWH and HIV negative persons, as well as on any differences in efficacy and safety of treatments and response to immunomodulators and finally on any differences in rates of metastatic disease and outcomes.

Expression of Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) in Non- Melanoma Skin Cancer: A Clinical and Immunohistochemical study

ABSTRACT Transient Receptor Potential Channel of Melastatin number 8 (TRPM8) is abnormally expressed in many cancers as lung, however little is known about TRPM8 expression in non-melanoma skin cancer (NMSC) including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). This work aimed to study TRPM8 expression in NMSC. It included 100 skin biopsies (50 normal skin as control group, 15 BCC and 35 SCC). Immunohistochemical staining for TRPM8 was done and results were correlated with clinicopathological characters. There was significant higher TRPM8 H-score in NMSC than control skin. On comparing SCC cases to control, there was significant positive TRPM8 expression, strong intensity, diffuse pattern, cytoplasmic and nucleo-cytoplasmic localization and higher range of H-score in SCC. In contrast, BCC showed significant lower TRPM8 positive expression when compared to control skin. Higher TRPM8 H-score in SCC showed significant positive correlation with large tumor size and poor tumor differentiation.TRPM8 may be implicated in pathogenesis of NMSC. Its association with bad prognostic characters; potentiates its role as prognostic biomarker and open new chances for therapeutic intervention in NMSC. TRPM8 antagonists may share in decreasing tumor growth and progression and may serve as potential target for tumor immunotherapy.

Exogenous sex hormones, menstrual and reproductive history, and risk of non-melanoma skin cancer among women: a systematic literature review and meta-analysis

Non-melanoma skin cancers (NMSC) are more frequent among men, but women (especially those aged < 40 years) have experienced steeper growth in their incidence rates in recent years. Hormonal factors were hypothesized to be playing a role in modulating NMSC risk, but the studies published to date provided conflicting results. We systematically reviewed and meta-analysed the studies focusing on the association between hormone-related characteristics (use of exogenous sex hormones, and aspects of menstrual and reproductive history) and the risk of NMSC among women. We included observational and experimental studies published in PubMed and EMBASE until February 2020. We calculated summary relative risk (SRR) and 95% confidence intervals (CI) by applying random effects models with maximum likelihood estimation, and used the I2 statistics to quantify the degree of heterogeneity of risk estimates across studies. Eleven independent studies encompassing a total of over 30,000 NMSC cases were included in quantitative analyses. No evidence of an increased NMSC risk emerged among ever vs. never users of oral contraceptives (SRR 1.13, 95% CI 0.88–1.45) or hormones for menopause (SRR 1.09, 95% CI 0.87–1.37). Likewise, age at menarche or at menopause and parity were not associated with NMSC risk. Heterogeneity across studies was low, and pooled results were comparable between NMSC subtypes. We found no evidence that hormonal factors play a role in the pathogenesis of NMSC among women.

Do Diet and Lifestyles Play a Role in the Pathogenesis of NMSCs?

Background and Aims: Literature highlights the role of risk factors like age, body mass index (BMI), tobacco smoking, alcohol intake and diet in the pathogenesis of several cancer types but little is known for non-melanoma skin cancers (NMSC). The aim of this epidemiological study was to evaluate the correlation between modifiable risk factors (BMI, metabolic panel, diet, lifestyle, medical history) and not modifiable risk factors (gender, age) and NMSC development. Methods: From February 2018 to September 2019, 162 patients affected by NMSC were compared to a group of 167 controls. A univariate and multivariate analysis was conducted to elaborate the data collected through face-to-face interviews. Results: While our evidence did not always reach statistical significance, NMSC study group patients exhibited high rates of analyzed risk factors (male gender aging over 55 years, high BMI, reduced physical activity) compared to the control group. Conclusions: Our study indicates that practicing more than 30 min of physical activity daily could be a protective factor against the NMSC onset. Other risk factors were not correlated with NMSC, but more evidence is needed to establish a possible link.

Personal solar ultraviolet radiation dosimetry in an occupational setting across Europe

Work-related solar ultraviolet radiation (UVR) is an important factor in the pathogenesis of non-melanoma skin cancer (NMSC). The World Health Organization, through the International Agency for Research on Cancer, has classified solar UVR as a group 1 carcinogen since 2012. The main problems encountered so far in the study of occupationally induced skin cancer include the lack of accurate occupational UVR dosimetry as well as insufficient distinction between occupational and leisure UVR exposure and underreporting of NMSC. The aim of this study was to collect long-term individual UVR measurements in outdoor workers across European countries. A prospective study was initiated through the European Academy of Dermatology and Venereology, Healthy Skin@Work Campaign, measuring UVR exposure doses at occupational settings of masons from five European countries. Measurements were performed for several consecutive months using the GENESIS-UV measurement system. The results identified alarming UVR exposure data. Average daily UVR doses ranged 148.40-680.48J/m2 in Romania, 342.4-640.8J/m2 in Italy, 165.5-466.2J/m2 in Croatia, 41.8-473.8J/m2 in Denmark and 88.15-400.22J/m2 in Germany. Results showed an expected latitude dependence with increasing UVR yearly dosage from the north to the south of Europe. This study shows that outdoor workers from EU countries included in this study are exposed to high levels of occupational solar UVR, vastly exceeding the occupational exposure limits for solar UVR exposure, considered to be 1-1.33 SED/day in the period from May to September. This finding may serve as an evidence-based recommendation to authorities on implementing occupational skin cancer prevention strategies.

Does the Autophagy Related Gene 7 (ATG7) Have a Role in Non-Melanoma Skin Cancer?

PurposeTo evaluate the role of autophagy related gene 7 (ATG7) in non-melanoma skin cancer.Subjects and MethodsThis retrospective and prospective case-control study was performed on 104 patients with non-melanoma skin cancer (NMSC) in addition to 20 apparently healthy subjects matched for age and sex as a control group. Multiple skin biopsies were taken for immunohistochemical evaluation of ATG7 expression.ResultsBoth epithelial and stromal ATG7 were expressed in all participants while all patients showed nucleocytoplasmic localization and controls showed both cytoplasmic and nucleocytoplasmic expression. In addition, significantly higher H-scores of ATG7 in both epithelium and stroma were detected in patients compared to controls (P<0.001).ConclusionATG7 nucleocytoplasmic topographic localization might be involved in the pathogenesis of NMSC, which can open the gate for new target therapy for this skin cancer.

UV-radiation as a Risk Factor for Non-melanoma Skin Cancer. Genetic Determinants of Carcinogenesis

The review presents modern data on the role of ultraviolet (UV) radiation in the pathogenesis of non-melanoma skin cancer (NMSC), the problem of THE risk of developing NMSC, in particular, squamous cell and basal cell skin cancer both in the population and in long-term repeated irradiation of phototherapy (PUVA therapy, UVB therapy, UVB-311 therapy) in patients with psoriasis. The paper considers the mechanisms of UV-induced cell damage by different spectral ranges (UVA, UVB) including the formation of photoproducts, damage to genomic DNA and other cellular structures, violation of the regulation of signaling pathways, the development of chronic inflammation, secondary immunosuppression. The review summarizes the results of large epidemiological studies discussing the role of gene polymorphisms in the homologous DNA repair XRCC3, gene telomerase TERT-CLPTMI, cytokine IL10 gene, MTHFR gene, encoding the folate synthesis, genes involved in pigmentirovanie MC1R, EXOC2, UBAC2 in the modulation of risk of carcinogenic effect of UV radiation. According to the authors’ opinion, the most vital and significant is data on the role of vitamin D receptor (VDR) gene polymorphisms as possible predictors of the risk of NMSC development. The further prospects of academic research on the cumulative role of the genome and environmental factors in the risk assessment of NMSC are revealed.

Non Melanoma Skin Cancer Pathogenesis Overview.

(1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.

Neuroendocrine factors: The missing link in non‑melanoma skin cancer (Review).

Non-melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun-protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun-exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well-known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene-related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α-melanocyte-stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.

Evaluation of Hypoxia Inducible Factor-1α and Glucose Transporter-1 Expression in Non Melanoma Skin Cancer: An Immunohistochemical Study.

Hypoxia Inducible Factor-1 (HIF-1) is a mediator enabling cell adaptation to hypoxia. It plays its role mainly through transcription of many target genes including Glucose Transporter-1 (GLUT-1) gene. The present work aimed at evaluating the pattern and distribution of HIF-1α and GLUT-1 in each case and control. A case-control and retrospective study was conducted on archival blocks diagnosed from pathology department as, Basal Cell Carcinoma (BCC, 20 cases), cutaneous Squamous Cell Carcinoma (SCC, 20 cases) and 20 normal site-matched skin biopsies from age and gender-matched healthy subjects as a control. Evaluation of both HIF-1α and GLUT1 expression using standard immunohistochemical techniques was performed on cut sections from selected paraffin embedded blocks. HIF-1α was expressed in 90%, 35% and 100% of normal skin, BCC and SCC tumour islands respectively. It was up regulated in both BCC and SCC compared with normal skin (p= 0.001, p<0.001 respectively). GLUT-1 was expressed in 100%, 70% and 100% of normal skin, BCC and SCC tumour islands respectively. It was down regulated in Non Melanoma Skin Cancer (NMSC) cases compared with normal skin (p=0.004). HIF-1α and GLUT-1 localization in tumour nests was central, peripheral or central and peripheral. Both HIF-1α and GLUT-1 showed variable expression in stroma, adnexa and inflammatory cells. No significant correlation was found between Histo (H) score or expression percentage values of HIF-1α and those of GLUT-1 in tumour islands or in overlying epidermis either in BCC or SCC. HIF-1α may have a role in NMSC pathogenesis through adaptation to hypoxia which results from excessive proliferation. GLUT-1 down regulation in NMSC may be explained by its consumption by proliferating tumour cells. The expression of HIF-1α and GLUT-1 in normal epidermis, stromal and adnexal structures needs further research.

How Wounding via Lasers Has Potential Photocarcinogenic Preventative Effects via Dermal Remodeling.

As the incidence of non-melanoma skin cancer (NMSC) is increasing, there is a growing need to identify effective preventive strategies. A recently proposed hypothesis states that NMSC photocarcinogenesis is tightly linked to insufficient insulin growth factor-1 expression by agglomerated senescent fibroblasts in geriatric dermis. This paucity of IGF-1 expression in senile skin allows basal keratinocytes to mitotically propagate their UVB-altered genome and potentially initiate an actinic neoplasm. Here we review the role of the dermal microenvironment in NMSC pathogenesis, describe the impact of fibroblast senescence on this process and discuss how laser-induced dermal wounding can be effectively used to prevent NMSC development in geriatric patients.

Farmers develop more aggressive histologic subtypes of basal cell carcinoma. Experience from a Tertiary Hospital in Northern Greece.

Ultraviolet radiation plays an important role in the pathogenesis of non-melanoma skin cancer. Outdoor workers, including farmers, experience higher exposure levels compared to the general population. Available literature data suggest that occupational ultraviolet exposure represents an independent risk factor for squamous cell carcinoma; whereas for basal cell carcinoma (BCC) this association still remains unclarified. To analyse the epidemiological, clinical and histological data of patients diagnosed with BCC, and correlate them with outdoor occupation in farmers. Individuals with histologically diagnosed BCCs, between September 2013 and September 2015, were included in the study. Their medical data, including epidemiological, clinical and histological characteristics, were recorded and analysed in conjunction with the occupation. Farmers were identified based on their specific public health insurance. Three hundred and forty patients, with 542 BCCs were included in the study. One hundred and twenty (35.3%) were farmers. Mean age of farmers was lower than non-farmers (66.0 ± 9.1 years vs. 75 ± 6.6 years, Mann-Whitney U-test, P < 0.001). Farmers had a sixfold higher probability for exhibiting photodamaged skin (OR = 6.02, 95% CI: 3.66-9.90, P < 0.001). Farmer workers were more likely to exhibit infiltrative or morpheaform BCC, but less likely to develop superficial BCC. Our results indicate a higher risk of earlier development of more aggressive histological subtypes of BCCs in farmers. Photodamage was also more common in this group. Primary and secondary prevention strategies focusing on outdoor workers, including farmers, are mandatory.

Abstract B055: The impact of rapamycin and tacrolimus treatment on resident CD8+ T-cell populations in cutaneous squamous cell carcinoma

Abstract Organ transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) development. Immunosuppressive agents, given to these patients to prevent organ rejection, are widely recognized to play a key role in the increased incidence of malignancy. However, different immunosuppressive agents, such as rapamycin and tacrolimus, which both prevent organ rejection, convey different risks of tumor formation. Using a UV-induced murine model of squamous cell carcinoma (SCC); HPV38 E6E7, we aim to determine whether these discrepancies are due to differences in the mechanism of immune suppression, in contrast to the much discussed direct effects of these drugs on tumor cells (i.e. immune-independent). Using customized rapamycin- and tacrolimus-incorporated feed to allow long-term administration, clinically relevant whole blood drug concentrations were obtained and validated using LC-MS/MS. Both systemic and local immunosuppression was functionally determined via adoptively transferred transgenic T-cell assay and skin allograft rejection profile, respectively. Notably however, preliminary data suggests phenotypic and functional differences of skin-residing T-cell subpopulations may exist when mice are treated with either rapamycin or tacrolimus, alluding to their potential role in the pathogenesis of NMSC. Short-term contact hypersensitivity responses (CHS) to OVA were abrogated in both rapamycin and tacrolimus-treated mice. However, prolonging the challenge phase enhanced the long-term CHS response in rapamycin-treated but not in tacrolimus-treated mice compared to normal feed controls. This enhanced response was correlated with an increased number of effector memory CD8+ T-cell population in the challenged ear skin. Using established chronic UV dosing schedules for SCC development in HPV38 E6E7 mice, tumor samples along with surrounding UV-exposed skin and fur-covered UV-protected skin samples were analyzed with FACs under the influence of these drugs. Preliminary data suggests that the formation of resident-memory CD8+ T-cells may be favored when treated with rapamycin, as higher percentages of CD8+ T-cells were present in the lesions of rapamycin-treated mice compared to tacrolimus and controls. In addition, LC-MS/MS analysis indicated that the concentration of rapamycin in the skin was significantly lower when compared to tacrolimus, whilst clinically relevant immunosuppressive concentrations of both drugs were maintained in the blood and kidneys. Through this project, we will expand our knowledge base regarding mechanisms of SCC formation in immunosuppressed patients. Citation Format: Ji-Won Jung, Paul J. Taylor, Fiona Simpson, Ian H. Frazer, James W. Wells. The impact of rapamycin and tacrolimus treatment on resident CD8+ T-cell populations in cutaneous squamous cell carcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B055.