Organ transplant recipients (OTRs) on cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK1/2 inhibitor, ruxolitinib. In human SCC cells, the greatest proliferative response to IL-22 and CSA treatment occurred in nonmetastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs and in SCC with high risk for metastasis. Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1, and STAT1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171807 | PMC |
| http://dx.doi.org/10.1172/jci.insight.120750 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
High-risk Prognostic Tumor Features of Squamous Cell Carcinomas in Organ Transplant Recipients Compared With the General Population.
JAMA Dermatol
August 2023
Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Article Synopsis
- This study investigates the differences in characteristics of squamous cell carcinomas (SCCs) between organ transplant recipients (OTRs) and the general population, focusing on high-risk features like tumor size and cellular differentiation.
- The research included two groups: OTRs from a specific study (STAR) and a broader population study (QSkin), both analyzed for SCCs diagnosed from 2012 to 2015.
- Key findings showed that SCCs in OTRs predominantly affected the head/neck area and had higher rates of aggressive features compared to those in the general population, highlighting the increased risk faced by these patients.
Squamous cell carcinomas in organ transplant recipients. Comparison of histopathological and clinical features of squamous cell carcinoma in patients after organ transplantation to immunocompetent patients.
Postepy Dermatol Alergol
October 2022
Dermatology and Venereology Clinic, Copernicus, Independent Public Healthcare Centre, Gdansk, Poland.
The occurrence of neoplasms is one of the most common complications and second most frequent cause of death in organ transplant recipients (OTRs). The most frequently occurring neoplasms are skin cancers, predominantly squamous cell carcinoma (SCC). However, the ratio between SCC and basal cell carcinoma (BCC) in OTRs differs in several studies depending on the follow-up time, country, environment and other factors.
View Article and Find Full Text PDFTopical treatment of actinic keratoses in organ transplant recipients: a feasibility study for SPOT (Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments).
Br J Dermatol
September 2022
Department of Dermatology, Barts Health NHS Trust, London, UK.
Background: The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients.
View Article and Find Full Text PDFSafe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.
Curr Oncol
January 2021
Department of Otorhinolaryngology-Head and Neck Surgery, Montefiore Medical Center, Bronx, New York, NY 10467, USA.
Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection.
View Article and Find Full Text PDFDestructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer.
Arch Dermatol Res
March 2022
Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!