Akbay Lab

Akbay Lab studies genetic and molecular events that lead to lung-tumor initiation and immune evasion.

Tumor cells and immune cells share limited nutrients in the environment. Using high throughput techniques and functional analysis we study the contribution of tumor cell metabolism to immune evasion.

    Small cell lung cancer (SCLC) is one of the most aggressive cancer types with exceptionally poor survival rates irrespective of stage. There has been minimal progress in the treatment of SCLC over the last 30 years. Recently PD-1 blocking antibody was approved to be used in combination with chemotherapy in SCLCs. However, for unknown reasons PD-1 blockade is effective in only a very small subset of SCLCs. We observed that SCLC cell lines and patient tumor tissue lack protein expression of ligands for the most potent NK cell activating receptor NKG2D and thus not visible to NK and T cells. We showed that epigenetic silencing contributes to the lack of NKG2DL expression in the neuroendocrine subtype of SCLC. Restoration of NKG2DL by treatment with an HDAC inhibitor upregulated NKG2DLs in lung cancer cell lines. Additionally, this treatment sensitized a syngeneic SCLC model to NK and T cell killing in vivo. Similar observations were made in another neuroendocrine tumor, neuroblastoma. We discovered a lineage-dependent mechanism of immune escape for SCLC and neuroblastoma and a pharmacological approach to activating anti-tumor innate immunity against this designated “recalcitrant cancer” (Zhu et al Can Res). Our current projects are focused on harnessing this vulnerability of SCLCs to target them to immune cell killing.

    Discovering immune evasion mechanisms

    Amino acid metabolism is recognized as a critical immune regulatory control point, which tempers T cell response. Tryptophan degradation limits innate and adaptive immune responses by depleting the tumor local microenvironment of tryptophan and by promoting the accumulation of kynurenine resulting from the catabolism of tryptophan. Similar to tryptophan metabolism, arginine degradation contributes to T cell suppression. While most cells can synthesize arginine from citrulline, T cells are dependent on extracellular arginine. Arginases and NOS are the main enzymes regulating extracellular arginine levels in the tissues. Though the exact role of activation of arginase across the different genomic subtypes of lung cancer is not fully understood, we showed that targeting arginase is an effective therapeutic strategy in Kras mutant lung cancers (Miret et al, JITC).

    Alterations in other metabolites such as Adenosine have also been implicated in immune suppression. We showed that EFGR mutations activate the Adenosine pathway and suppress anti-tumor immunity through the accumulation of adenosine in the tumor tissue and increased uptake by the T cells. Our current projects are focused on understanding the role of these altered metabolic pathways in immune resistance in genomically classified tumors using transgenic, syngeneic, and humanized cancer models.

    We discovered a novel splice isoform of major immune checkpoint protein PD-L1. This isoform retains part of an intron and lacks the transmembrane domain. Unlike the full-length protein does not localize to the membrane but secreted into the media or circulation. This soluble isoform still retains the ability to bind to the PD1 receptor and is able to suppress T cell activation.

    Discovering novel immune checkpoints

    Meet the Principal Investigator

    Esra Akbay, Ph.D.

    Esra Akbay, Ph.D.

    Assistant Professor, Department of Pathology

    Dr. Akbay earned her Ph.D. from UT Southwestern Medical Center and received her postdoctoral training in translational lung cancer research from the Dana-Farber/Harvard Cancer Center.

    Lab Members

    Daniella Rin Yang, B.S.

    Research Technician II
    Undergraduate: Stony Brook University

    Daniella Rin Yang, B.S.

    Qing Deng, Ph.D.

    Post-Doctoral Fellow
    Ph.D.: Shanghai Jiao Tong University

    Qing Deng, Ph.D.

    Mingrui Zhu, B.S.

    Ph.D. Student
    Undergraduate: Wuhan University

    Mingrui Zhu, B.S.

    Ryan Kowash, B.S.

    Ph.D. Student
    Undergraduate: Dickinson College

    Ryan Kowash, B.S.

    Mathew Bender, B.S.

    Research Technician II - Lab Manager
    Undergraduate: Trinity University

    Current position: Medical Student, Texas Tech University

    Mathew Bender, B.S.

    Buse Eglenen Polat, M.D.

    Post-Doctoral Researcher
    Medical degree:  Koç University Medical School, Istanbul

    Current position: Internal Medicine Resident, West Virginia University

    Buse Eglenen Polat, M.D.

    William Huang

    William Huang

    Ph.D. Student

    Undergraduate: 

    William Huang

    All Publications

    Lab Fun

    Contact the Akbay Lab

    Phone: 214-648-4159
    Email

    Mailing Address
    UT Southwestern Medical Center
    5323 Harry Hines Blvd.
    Dallas, Texas 75390-9072

     

    Join Our Lab

    Be part of the impact we're making on cancer research.

      A postdoctoral position focused on studying the lung tumor microenvironment and immunotherapy in lung cancer is available in our laboratory. Specific emphasis will be placed on understanding the role of oncogenes and tumor suppressors in evading anti-tumor immunity. This work will incorporate the use of cell culture, animal models, and clinical specimens.

      Candidates must hold Ph.D. and/or M.D. degrees. A cancer research background and a track record of leading projects to publication are preferred. Candidates who have experience with flow cytometry, molecular biology, mouse models, and cell culture techniques are encouraged to apply. The postdoctoral fellow will be expected to direct independent projects in a multi-disciplinary setting and collaborate with the other members of the laboratory.

      Interested individuals should send a CV, a statement of interest, and a list of three references to Dr. Esra Akbay.

      We are accepting graduate students! Students already enrolled in graduate school can email Dr. Akbay for scheduling rotations.

      Prospective students need to apply to the Ph.D. or combined M.D./Ph.D. Programs in UT Southwestern Graduate School, then contact us about rotations.