Prof. Dr. Popescu Iulia

Prof. Univ. Dr. Iulia Popescu
Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA

Cutaneous complications – Squamous cell carcinoma of the skin after lung transplant in IPF recipients with short telomeres

Author: Iulia Popescu
Division of Pulmonary Allergy and Critical Care, Sleep Medicine, Department of Medicine,University of Pittsburgh, PA, USA

Rationale: Lung transplant is now an established modality for a broad spectrum of end-stage pulmonary diseases. Lung transplants become more common of post-transplant dermatologic complications. With the increasing use of lung transplant, pulmonologists and dermatologist must be aware of the common as well as the unique posttransplant dermatologic complications, because of immunosuppression, infections, and a variety of medications along with environmental exposures. We describe here the pathogenesis and clinical manifestations of dermatologic complication along with epidemiological characteristics found in lung transplant recipients, with a focus on increased incidence of squamous cell carcinoma (SCC) and in idiopathic pulmonary fibrosis (IPF) patients with short telomeres (TL) who undergo lung transplantation. We have recently shown that short telomeres are common in IPF patients who undergo lung transplantation. Because patients with short telomeres are at increased risk for developing squamous cell carcinoma (SCC), we investigated the incidence of SCC in a retrospective case-control cohort of 144 lung transplant recipients (LTRs). We compared short telomere length (short TL; ≤10th percentile) IPF-LTRs to long TL IPF-LTRs and non-IPF-LTR controls.
Methods: Data were extracted on a retrospective cohort of 72 IPF-LTRs (49 short telomeres, 23 long telomeres) and 72 age-matched non-IPF-LTR controls (median age 63 and 61years, respectively). Lymphocyte and granulocyte telomere length (TL) were measured using flow cytometry and fluorescence in-situ hybridization (flowFISH). Genetic assessment was done using WGS or a targeted sequence panel. TL from WGS was measured using TelSeq software.
Results: A cohort of IPF-LTRs who underwent transplant between 2005 and 2021 was identified retrospectively at our institution, in which flowFISH revealed 49/72 (68%) had short TL. TelSeq from WGS samples revealed a significantly shorter TL for the IPF-LTR cohort compared to the age adjusted mean (p<0.001). Genetic characterization for the 7 telomere maintenance genes showed that 19/72 (26%) IPF-LTRs had rare variants in the telomere associated genes and all 19 had short-TL. IPF-LTRs had a significantly higher incidence of developing SCC post-lung transplant with30/72 (42%) compared to non-IPF LTRs 9/72 (13%) p=<0.0001. Among the IPF-LTRs, short-TL IPF-LTRs had increased occurrence of SCC compared to long-TL IPF-LTRs (p=0.0042). There was no significant difference in squamous cell carcinoma diagnosis in IPF-LTRs with an identified rare gene variant (47% vs 36%; p=0.3769). Short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued from three to two drug regimens due to cytopenia’s compared to non-IPF controls (p=0.0375). IPF-LTRs with squamous cell carcinoma were more likely to have immunosuppression agents discontinued from three to two drug regimens compared to non-IPF controls (77% vs 44%; p=0.0662). There was no significant difference in mortality due to squamous cell carcinoma between IPF-LTRs and non-IPF controls (p=0.1447), however all 6 IPF mortalities had short-TL (6/26; 23%) with 3/6 (50%) having a rare variant and immunosuppression discontinued.
Conclusions: IPF-LTRs with short-TL are at increased risk of developing squamous cell carcinoma post-transplant and these patients had higher incidence of immunosuppression medications discontinuation and higher mortality rate. Therefore, telomere length measurement is useful in identifying these IPF-LTRs at risk for developing post-transplant squamous cell carcinoma.

Short CV

I am a Associate Professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh in Dr. John McDyer’s laboratory. I have significant experience in transplant and viral immunology. My work has focused on T cell mechanisms of rejection, tolerance, and host immunity to viruses such as CMV, EBV and HIV, including the measurement of lung mucosal responses. I have focused on CMV-specific T cell immunity in lung transplant recipients in a leading clinical transplant program. I am CO-I on a U01 award (AI125050-Dr. McDyer) to perform a novel clinical trial to perform tandem lung and bone marrow transplantation in select individuals with primary immunodeficiencies and end-stage lung disease, and to perform mechanistic pathogen-specific and alloimmune tolerance studies in these study participants. In U01AI125050 I measure systemic and lung pathogen-specific immune responses. As immunologist my focuses are on mechanisms of CMV-specific lung mucosal/systemic immunity and viral control, demonstrating an important role for the Type-1 transcription factor T-bet and other immune parameters. I also study immune mechanisms of allograft rejection/tolerance in lung transplantation with an established divisional research group performing studies in the human studies. I also perform work on Dr. McDyer and Dr. Kirks’ collaborative U01 award (HL121814) to study immune mechanisms of HIV-associated COPD. I am the Co-I on an R01 award HL133184-01 (Dr. McDyer), “Role of F-box Proteins in Lung Transplantation.” In addition, common to these experimental systems above, Dr. McDyer’s laboratory is highly proficient in measuring lung mucosal and systemic viral-specific and allospecific multifunctional T cell immunity and phenotyping in lung transplant recipients. I have a good track record of training medical students and fellows and junior faculty in Dr. McDyer’s lab. the field of lung transplant immunology. Pertinent to this proposal I also have significant experience assessing human alloimmunity, using flow cytometry, in addition to viral immunity, and evaluate the phenotype of T cells, proliferation and effector multifunction. In addition, I am very experienced in ELISA and ELISPOT assays to measure inflammatory responses. Recently, we showed that IPF lung transplant recipients with short telomeres have impaired CMV T cell immunity. Here at Pitt, Dr. Alder, Dr. Snyder, Dr. Chen, Dr. Iasella and Dr. Popescu have a track record of working closely together. Therefore, based on my established and current role in Dr. McDyer’s laboratory and my expertise in transplant immunology in the field of lung transplantation makes me well-suited to fulfill my role as Co-I on this project R01 project, “The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes”.

EDUCATION and TRAINING
1981-1985 – C.A. Rosetti – Bachelor of Science, 1985, Biology-Chemistry Bucharest, Romania
1986-1992 – Polytechnic University Master’s Degree, 1992, Faculty of Chemistry Bucharest, Romania
1996-2000 – University of Bucharest, Ph.D. in Life Science 2000, Faculty of Chemistry, University of Bucharest, Romania
2000-2001 – Research Scientist III – Dept. of Cellular, Immunology and Signal Transduction, Centre of Immunology, Institute of Virology, Bucharest, Romanian
2001-2006 – Postdoctoral Research Associate – University of Pittsburgh, Dept of Surgery
2010-2012 – Sr. Staff Scientist/Technical Application Specialist, Cellular Technology, Limited, CTL, Shaker Heights, OH
2/2012-4/2014 – Visiting Research Associate/ Manager Flow Cytometry Core, Division of Pulmonary, University of Pittsburgh, Pittsburgh, PA, USA
5/2012-6/2014 – Research Associate / Manager Flow Cytometry Core Division of Pulmonary, University of Pittsburgh

APPOINTMENTS and POSITIONS ACADEMIC
5/2006-9/2006 – Visiting Research Instructor of Surgery, Dept of Surgery, University of Pittsburgh
10/2006-4/2010 – Research Instructor of Surgery, Dept of Surgery, University of Pittsburgh
7/2014-3/2015 – Visiting Research Assistant Professor of Medicine/ Manager Flow Cytometry Core, Division of Pulmonary, University of Pittsburgh
4/2015-3/2020 – Research Assistant Professor of Medicine, Division of Pulmonary, University of Pittsburgh
3/2020-present – Research Associate Professor of Medicine, Division of Pulmonary, University of Pittsburgh

MEMBERSHIPS in PROFESSIONAL and SCIENTIFIC SOCIETIES
-Member – American Society of Transplantation (AST) 2006-present
-Member – American Immunology Association (AIA) 2007-present
-Member – European Association for Cancer Research (EACR) 1998-present
-Member – Federation of European Biochemical Societies (FEBS) 1990-present
-Member – Romanian Society of Immunology (SNI) and Dermatology 1986-present
-Member – International Society of Heart and Lung Transplantation 2019-present