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. Currently, we are actively involved in three such armored CAR-T or TCR-T trials for various solid tumor treatments.Īccompanying 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. We also believe the T cell is a perfect platform to integrate genomic engineering for combinatory cancer therapy. 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. Indeed, some of them greatly enhance CAR-T’s anti-tumor function. 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. Expression profiling and functional screening in the lab have produced many candidates to make T cells smarter and stronger. Identifying miRNA functions and targets is our path to discovering novel proteins, or novel functions of known proteins, in T cell regulation. During the last decade, my laboratory invested heavily in the microRNA (miRNA) field, deeming miRNAs a unique tool for T cell biology discovery. 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. The expanding boundary of T cell biology is the frontier of cancer immunotherapy. The next step is to identify those evil envoys sent out by tumors carrying signals for systemic immune suppression.
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. Moving beyond the local microenvironment, our previous studies also demonstrated that tumors remotely modulate T cell antigen-priming events in the spleen. 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. Our recent single cell RNA sequencing study depicted complex pathways to develop T cell memory intratumorally. 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. By this scientific precept, we study how tumors inhibit T cell-mediated immunity both locally and systemically. We regard the tumor as an acquired immunosuppressive organ. 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. Meanwhile, current limitations of these advanced treatments pinpoint fundamental knowledge deficits in basic T cell biology, especially in the context of tumor-carrying patients. 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.
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