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Murad Mamedov, Ph.D.

  • Assistant Professor, Center for Advanced Therapeutics

Murad Mamedov is an immunologist studying immune stress sensing in cancer, with a focus on human γδ T cells. Mamedov has been at the forefront of applying CRISPR screens, functional genomics, and other cutting-edge technologies to dissect one of the oldest mysteries in immunology: how do γδ T cells protect us from cancer and how can we apply these findings therapeutically?

Mamedov completed his B.S. in biology and philosophy at Georgetown University. As an immunology Ph.D. student with Dr. Mark Davis at Stanford University, he studied the protective role of γδ T cells during malaria. During his postdoctoral fellowship with Dr. Alex Marson at UCSF and Gladstone Institutes, Mamedov developed CRISPR screening platforms and functional genomics approaches to examine immune stress sensing of tumor cells by human γδ T cells.

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The Mamedov Laboratory

215-898-3700
Murad Mamedov image courtesy Michael Short, Gladstone Institutes

Photo courtesy Michael Short, Gladstone Institutes

The Mamedov Laboratory

Cellular and systemic stresses within the tumor microenvironment trigger responses and adaptations in cancer cells that are generally conserved across tissues and patients. γδ T cells play a unique role as immune stress sensors by recognizing stress-induced ligands on cancerous, inflamed, and infected cells across tissues through their highly diversified γδ T cell receptors (TCR) and other receptors. Thirty-eight years after their discovery, γδ T cells remain poorly understood despite becoming a strong focus of cancer immunotherapy efforts. Like antibodies, γδTCRs bind to their targets directly without MHC presentation, allowing for allogeneic γδ T cell therapies. Tumor-infiltrating γδ T cells have been shown to be strongly associated with favorable outcomes in cancer patients. However, while thousands of TCR targets of conventional CD4 and CD8 T cells are known, comparatively very few γδTCR ligands have been described, hindering our grasp of γδ T cell function during cancer.

The Mamedov Lab uses a combination of functional genomics, CRISPR screens, and immunology approaches to explore therapeutically relevant questions around tumor-immune interactions with a focus on γδ T cells, including: How does the immune system surveil for cellular and systemic stress in cancer cells?

We seek to unravel three distinct layers that determine interactions between cancer cells and γδ T cells: (1) cancer targets recognized by human γδTCRs; (2) stress-induced regulation of γδTCR ligands; and (3) genetic programming and reprogramming of critical γδ T cell functions under various tumor environments.

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Research

STRESS-INDUCED REGULATION OF CANCER TARGETS

Stress-induced antigens are surprisingly underutilized therapeutic cancer targets. Tumors are routinely exposed to cellular stresses that increase or activate specific endogenous proteins, including butyrophilin (BTN) family proteins, that are targeted by human and mouse γδ T cells. Building on our previous work (Mamedov et al., Nature), we will further elucidate metabolic, genetic, epigenetic, and post-translational regulatory mechanisms of BTN2A1, BTN3A1, and tissue-restricted BTN proteins on the cancer cell surface, which are required for the unique immunosurveillance performed by human γδ T cells.

DISCOVERY OF NOVEL γδ T CELL CANCER LIGANDS

Multiple lines of evidence indicate that many ligands recognized by diverse γδ T cell receptors (TCRs) remain undiscovered. Previous efforts to readily identify targets of expanded TCR clones have been hampered by the lack of high-throughput technologies enabling such discovery efforts. There is finally an intersection of sufficiently powerful tools (CRISPR screening, large protein libraries, and so on) and sufficient understanding of γδ T cell biology to crack open one of the major and longstanding problems in immunology: what is the larger set of ligands recognized by the extensive repertoire of γδTCRs and how are these specificities contributing to control of cancer and other diseases? Using different cutting-edge technologies that we previously established and that we plan to adapt to this problem, we will uncover novel cancer ligands of human γδ T cells and target them therapeutically.

FUNCTIONAL GENOMICS AND ENGINEERING OF HUMAN γδ T CELLS

Apart from the different modes of TCR-ligand engagement, γδ T cells exhibit many important functional differences from conventional CD4 and CD8 T cells that are advantageous for targeting and killing tumors, for example rapid response rates, solid tumor infiltration, and combining adaptive and innate immune functionality. Using genome-wide CRISPR screening and functional genomics, we will map out the genetic circuitry behind these anti-tumor γδ T cell functions. We will then use the same tools of gene editing to intervene upon these genetic circuits and engineer primary human γδ T cells for improved anti-cancer activity.

Selected Publications

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection

Mamedov, M., Vedova S., Freimer, J., Sahu, A., Ramesh, A., Arce, M., Meringa, A., Ota, M., Chen, P., Hanspers, K., Nguyen, V., Takeshima, K., Rios, A., Pritchard, J., Kuball, J., Sebestyen, Z., Adams, E., Marson, A. “CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.” Nature 2023 Sept; 621(7977):188-195. DOI: 10.1038/s41586-023-06482-x. PMID: 37648854. PMCID: PMC11003766

A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence

Murad M., Scholzen, A., Nair, R., Cumnock, K., Kenkel, J., Oliveira, J., Trujillo, D., Saligrama, N., Zhang, Y., Rubelt, F., Schneider, D., Chien, Y., Sauerwein, R., Davis, M. “A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence.” Immunity 2018 Feb 20;48(2):350-363.e7. doi: 10.1016/j.immuni.2018.01.009.

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