Faculty Bibliography

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) is an organization of more than 500 physicians and scientists focused on the treatment of cutaneous malignancies following solid organ transplantation and in other forms of immunosuppression. It is well known that solid organ transplant recipients (SOTRs) have an approximate 100-fold increase in the risk of developing skin cancer with consensus guidelines recommending these patients be managed as high risk for local recurrence and metastasis associated with poor outcomes. In September 2018, ITSCC and its European counterpart, the Skin Care in Organ Transplant Patients-Europe (SCOPE), held their biennial scientific retreat in Essex, MA to discuss novel findings in the pathogenesis of cutaneous malignancy including new treatment and prevention strategies in this at risk population for significant morbidity and mortality from their cutaneous disease. This meeting report is a summary of the novel findings discussed.

BACKGROUND:Staging systems for cutaneous squamous cell carcinoma (CSCC) include Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer staging system, eighth edition (AJCC-8). OBJECTIVE:To evaluate and compare AJCC-8 and BWH staging systems for CSCC in immunosuppressed patients. MATERIALS AND METHODS/METHODS:A retrospective cohort study of immunosuppressed patients diagnosed with primary CSCC from 2012 to 2016. The main end point was any poor outcome (PO), which included local recurrence, nodal metastasis, and disease-specific death. RESULTS:Fifty-eight immunosuppressed patients had 263 CSCCs. Fifty percent of tumors were AJCC-8 T1, 44.7% T2, and 4.8% T3. Fifty percent of tumors were BWH T1, 48.5% T2a, 1.3% T2b, and 0.4% T3. Risk of PO for AJCC-8 was 1.7%, 8.8%, and 36.4% for T1, T2, and T3, respectively (p < .01). Risk of PO for BWH was 1.8%, 9.9%, 33.3%, and 100.0% for T1, T2a, T2b, and T3, respectively (p < .01). Thirty-six percent of AJCC-8 T3/T4 tumors had POs compared with 5.1% in low T1/T2 stages (p = .002). Fifty percent of BWH T2b/T3 tumors had POs compared with 5.3% in low T1/T2a stages (p = .01). CONCLUSION/CONCLUSIONS:AJCC-8 and BWH staging systems stratify CSCC with similar distinctiveness, homogeneity, and monotonicity for immunosuppressed patients.

BACKGROUND:The management of skin cancers has evolved with the development of Mohs micrographic surgery and a greater emphasis on surgical training within dermatology. It is unclear whether these changes have translated into innovations and contributions to the reconstructive literature. OBJECTIVE:To assess contributions from each medical specialty to the cutaneous head and neck oncologic reconstructive literature. METHODS:The authors conducted a systematic review of the head and neck reconstructive literature from 2000 through 2015 based on a priori search terms relating to suture technique, linear closure, advancement, rotation, transposition and interpolation flaps, and identified the specialty of the senior authors. RESULTS:The authors identified 74,871 articles, of which 1,319 were relevant. Under suture technique articles, the senior authors were primarily dermatologists (58.2%) and plastic surgeons (20.3%). Under linear closure, the authors were dermatologists (48.1%), plastic surgeons (22.2%), and otolaryngologists (20.4%). Under advancement and rotation flaps, the senior authors were plastic surgeons (40.5%, 38.9%), dermatologists (38.1%, 34.2%), and otolaryngologists (14.4%, 21.6%). Under transposition and interpolation flaps, the senior authors were plastic surgeons (47.3%, 39.4%), dermatologists (32.3%, 27.0%), and otolaryngologists (15.3%, 23.4%). CONCLUSION/CONCLUSIONS:The primary specialties contributing to the cutaneous head and neck reconstructive literature are plastic surgery, dermatology, and otolaryngology.

Background: Immune response is key in defense against cutaneous squamous cell carcinoma (cSCC). We aim to better target T cell killing to treat cancer. Method(s): CD8+ tumor infiltrating lymphocytes (TILs) obtained from fresh SCC tumor specimens from immunocompetent (n=5) versus organ transplant recipients (OTRs; n=6) were subject to single-cell RNA profiling and T-cell receptor (TCR) sequencing. Data were analyzed using scSeqR. Result(s): CD8+ TILs were clustered based on gene expression as follows: effector T cells (GZMA, GZMB, IFN-gamma); naive T cells (CCR7, LEF1, TCF7, IL7R); exhausted T cells (BTLA, CTLA4, PDCD1, TIM3, LAG3); and regulatory T cells (FOXP3, STAT3, TNFSRF). CD8+ TIL clonotypes show potential for response to known and uncharacterized antigens. CD8+ TILs from OTRs exhibited more homogeneous gene expression compared with immunocompetent patients. Regulatory and exhausted T cells were reduced in OTRs. TILs from both OTRs and immunocompetent patients showed clonality. However, more TCR clonotypes were observed in immunocompetent patients (mean = 1140) than OTRs (mean = 544). We analyzed common beta TCR from SCC via multiple bioinformatics-based approaches. Clonotypes common to more than one SCC from immune competent patients included breast cancer-associated keratin 19 and proliferation-associated striatin. OTR clonotypes included tumor-suppressor associated MOB kinase 1A and breast cancer-associated ADAM9. Conclusion(s): CD8+ TILs from cSCC showed clonotype restriction, implying T cell mediated anti-tumor response. We will refine our understanding of the SCC T cell landscape and identify and screen neoantigens with the goal of developing rational T cell-based cancer therapy.

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.