Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
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Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.
Published Version (Please cite this version)
Huang, De, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, et al. (2022). Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression. Nature cell biology, 24(2). pp. 230–241. 10.1038/s41556-021-00820-9 Retrieved from https://hdl.handle.net/10161/26251.
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Recent clinical success in cancer immunotherapy, including immune checkpoint blockades and chimeric antigen receptor T cells, have settled a long-debated question in the field: whether tumors can be recognized and eliminated by our own immune system, specifically, the T lymphocyte. Meanwhile, current limitations of these advanced treatments pinpoint fundamental knowledge deficits in basic T cell biology, especially in the context of tumor-carrying patients. Aiming to develop new immunotherapies against cancers, and interconnected with clinical trials executed by clinician collaborators and immunogenomic tools developed in house, my research program rests on three pillars – the T cell, the Tumor Microenvironment, and Immunotherapy.
We regard the tumor as an acquired immunosuppressive organ. By this scientific precept, we study how tumors inhibit T cell-mediated immunity both locally and systemically. Our early TCR repertoire profiling of gastric tumors and tumor-free patient mucosa revealed the correlation between tissue resident T cell diversity and patient survival. Our recent single cell RNA sequencing study depicted complex pathways to develop T cell memory intratumorally. Currently, aided by bioinformatics and animal models, we are actively dissecting signaling pathways, transcription regulatory networks, and epigenetic programs governing T cell differentiation in the tumor microenvironment. Moving beyond the local microenvironment, our previous studies also demonstrated that tumors remotely modulate T cell antigen-priming events in the spleen. This ongoing in-depth investigation has gradually unveiled the profound impact of this “tele-education”: established tumors hijack hematopoiesis to protect themselves against T cell surveillance. The next step is to identify those evil envoys sent out by tumors carrying signals for systemic immune suppression.
The expanding boundary of T cell biology is the frontier of cancer immunotherapy. The contrast between the unprecedented success of T cell-based therapies for blood malignancies and their repeated failures against solid tumors vividly highlights our prevalent challenges: to understand how T cells can infiltrate tumors; how infiltrated T cells can resist microenvironmental suppression; and how activated T cells can form persistent memory to restrict tumor development and metastasis. During the last decade, my laboratory invested heavily in the microRNA (miRNA) field, deeming miRNAs a unique tool for T cell biology discovery. Identifying miRNA functions and targets is our path to discovering novel proteins, or novel functions of known proteins, in T cell regulation. Expression profiling and functional screening in the lab have produced many candidates to make T cells smarter and stronger. Due to their size, these miRNA candidates can be easily combined with targeting moieties to armor T cells, and we have incorporated these small weaponries, and introduced genomic manipulations on their downstream targets, into CAR-T cells for pre-clinical studies. Indeed, some of them greatly enhance CAR-T’s anti-tumor function. As a general principle, we believe that it is necessary to empower transferred CAR T or TCR-T cells with enhanced functionality against solid tumors. We also believe the T cell is a perfect platform to integrate genomic engineering for combinatory cancer therapy. Currently, we are actively involved in three such armored CAR-T or TCR-T trials for various solid tumor treatments.
Accompanying these trials, and other immunotherapies carried out by colleagues on campus and world-wide, we design and execute comprehensive immune monitoring procedures to rationalize successes and failures. Clinical observations are smoothly deconstructed into basic but intriguing T cell questions for us to answer, and answers generated on the bench directly inform T cell designs in future trials. This is our closed circle of research and day-to-day operation.
The current research in the Wang laboratory mainly focuses on the elucidation of molecular nature and signaling mechanisms associated with the initiation of cellular senescence. In addition, we continue to study changes in tumor microenvironment that promotes tumor progression and metastasis, particularly how tumor cells interact with the immune system. Ultimately, we hope that our studies in these areas to lead to the development of novel therapeutics for the treatment of various types of human cancer.
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