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101. Targeting Loss of p19, not p16, Reprograms Tumor and Systemic Immunity in Pleural Mesothelioma

*Andrea Wolf Invited Discussant
The Icahn School of Medicine at Mount Sinai
New York, NY 
United States  - Contact Me

Andrea Wolf is Director of the NY Mesothelioma Program and Associate Professor of Thoracic Surgery at the Icahn School of Medicine at Mount Sinai.  She graduated Cum Laude from Princeton and earned highest honors at Harvard Medical School. She served as Chief Resident in Surgery at the MGH and Cardiothoracic Surgery at the Brigham and Women’s Hospital, where she completed a Thoracic Oncology Research Fellowship while earning her MPH at the Harvard School of Public Health.  She has expertise in surgery for pleural mesothelioma and VATS lobectomy, and research interests in mesothelioma, health care disparities, and lung cancer.  She and her team at the NY Mesothelioma Program received the 2020 International Association for the Study of Lung Cancer Care Team Award and she was honored with the 2022 Absestos Disease Awareness Organization Irving J. Selikoff Award. She has presented at numerous national and international meetings, is co-editor of the third edition of Sugarbaker’s Adult Chest Surgery and has published extensively on pleural mesothelioma and lung cancer.  She loves to run and has one son, who is a superhero.

♦Hyun-Sung Lee Abstract Presenter
Baylor College of Medicine
Houston, TX 
United States  - Contact Me

Dr. Hyun-Sung Lee is an Assistant Professor in the David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery at Baylor College of Medicine (BCM). Dr. Lee has experienced more than 10 years to treat lung cancer and esophageal cancer as a thoracic surgeon, 3 years of research in the Department of Systems Biology at UT MD Anderson Cancer Center, and 5 years of immunology at BCM. Currently he is the Director of Systems Onco-Immunology Lab (SOIL) at BCM. He is particularly enthusiastic about “Systems Immunology” in the field of immuno-oncology with specific experience in comprehensively integrating high dimensional single-cell time-of-flight mass cytometry (CyTOF), imaging mass cytometry (IMC), mass spectrometry, single cell multiomics, and next-generation sequencing data. He has generated comprehensive analyses of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using CyTOF and non-small cell lung cancer (NSCLC) using RNA sequencing data. He has applied innovative immunoproteomic and immunogenomic approaches to this framework to understand mechanisms underlying clinical outcomes and response to immunotherapy in these diseases. Dr. Lee continues to characterize and unravel the cellular immune network by analyzing human and mouse single-cell data, correlating immune composition with immunogenomic determinants to predict clinical prognosis and response to checkpoint immunotherapy. His overarching goals are to identify potential therapeutic targets to overcome resistance to checkpoint immunotherapy and to investigate the cellular mechanism of tumor immunity and autoimmunity after immunotherapy by applying “comprehensive and integrated systems immunology” approaches.

Sunday, May 7, 2023: 7:15 AM - 7:30 AM
15 Minutes 
Los Angeles Convention Center 
Room: 408B 

Abstract

Objective: Recently we reported that cyclin-dependent kinase inhibitor 2a (CDKN2A)-depleted malignant mesothelioma (MM) is resistant to immune checkpoint blockade (ICB) and CDK4/6 inhibitors (CDK4/6i) improved primary resistance to ICB. CDKN2A, which is the most altered genomic locus in MM, encodes p14 (p19 in mouse) and p16. P16-cyclin D-CDK4/6-Rb and p14-MDM2-p53 pathways inhibit cell cycle and apoptosis, respectively (Fig.1A). However, resistance to CDK4/6i is considered a near-inevitability in a real world. Thus, there are still unmet needs to decipher deeper mechanisms to overcome ICB resistance.
Methods: Given the synteny between human 9p21.3 and murine 4C4 (Fig.1B), p16- or p19-overexpressing mouse AB1 MM cell lines (AB1_p16OE vs. AB1_p19OE) were generated to investigate mechanisms to overcome Cdkn2a-related ICB resistance (Fig.1C). We performed mRNA sequencing for molecular characterization. Furthermore, we compared the alteration of the tumor ecosystems and systemic immunity between AB1_p16OE or AB1_p19OE in immunocompetent BALB/c mice by using imaging and time-of-flight mass cytometry (CyTOF). We also compared the efficacy of dual PD-1 and CTLA-4 blockade on these MM tumors.
Results: Transcriptome analysis showed that AB1_p19OE had a distinct gene expression pattern compared with AB1_p16OE and AB1_wild cell lines. Overexpression of p19 led to the increase of Cd80 and chemokines Cxcl10 and Ccl4, which are involved in lymphocyte recruitment. In contrast, cell cycle-related genes, Cdk2 and Ccne1, and the immunosuppressive cytokine Tgfb1 were markedly decreased in AB1_p19OE cells (Fig.1D). Our in vivo experiments showcased a novel molecular mechanism of regulation of the tumor ecosystems that AB1_p19OE tumors contained lymphocyte aggregates, but AB1_p16OE tumor did not (Fig.1E). We evaluated the topographical expansion of T cells from the tumor to circulation in AB1_p16OE and AB1_p19OE tumors. Mouse CyTOF data showed that PD-1(+)CTLA-4(+) T cells were abundant in tumors (Fig.1F). Interestingly, AB1_p19OE tumors revealed the topographical expansion of CD4 and CD8 effector memory T cells from the tumor to PBMC (Fig.1F) and had a better response to dual ICBs (Fig.1G).
Conclusions: We have identified a novel therapeutic target, p19 in mice or p14 in humans, to sensitize tumors to ICB. This finding could help provide a rationale for combination treatment of ICB with MDM2 inhibitors to restore the function of p14 to treat MM patients with CDKN2A loss.

Presentation Duration

7 minute presentation; 7 minute discussion 

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