Blood-borne metastasis accounts for the bulk of morbidity and mortality of cancer patients. Rare disseminated tumor cells (DTCs)  in blood or other body fluids hold the key to understanding the process of human cancer metastasis. We are developing high-throughput technologies for full-spectrum DTC identification from patients with a variety of cancer types through exploiting common features of all cancer cells, including aberrant metabolic functions or genomic alterations. We are investigating the molecular signatures, functional activities, and metastatic potentials of these rare DTCs with the aim of understanding their diagnostic and prognostic values in the clinic.

An important arm in this direction is the blood-based neoantigen and cognate TCR discovery for cancer immunotherapy. The recent breakthrough in cancer immunotherapy brings exciting clinical benefit for patients with different malignancies through effectively harnessing the antitumor immune responses of human T cells. The ability of endogenous T cells to recognize and destroy tumor cells relies on the interaction between TCR and tumor-specific neoantigens derived primarily from mutant genes and presented in the MHC molecules on the surface of tumor cells. Resolving neoantigen and cognate TCR repertoire evolvement over the course of treatment, is central to understanding the dynamic interactions between tumor and immune cells. However, such work normally requires fresh (or snap frozen) tumor materials from which the tumor tissue can be sequenced and tumor-infiltrating lymphocytes can be isolated and expanded. Unfortunately, the availability of fresh (or snap frozen) tumor tissue biopsies is a significant limiting factor for personalized immunotherapy. The molecular profile of tumors evolves over time. But repeated biopsy sampling is invasive and seldom feasible for patients with many cancers. 

We are developing toolkits for blood-based neoantigen and cognate TCR discovery through the use of DTCs and match blood lymphocytes. These tools enable clinicians to repeatedly and non-invasively interrogate the neoantigen/cognate TCR repertoires and dynamic evolution of the anti-tumor immunity over the course of immunotherapies via serially collected blood samples, with the potential to deliver a clinically translatable approach in which all that is needed to develop tumor vaccines or tumor-specific T cell products is a simple blood draw.