Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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Page 38 of 51 September/October 2018 Clinical OMICs 37 A team of researchers from the University of Pennsyl- vania (UPenn) School of Medicine revealed that the exosomes (extracellular vesicles) that contain programmed death-ligand 1 (PD-L1), released by melanoma cells, are found far beyond the tumor microenvironment and could be purified from the plasma of patients. James L. Gulley, M.D., Ph.D., a senior investigator and the chief at the genitourinary malignancies branch of the National Cancer Institutes said "we have been so used to thinking about the PD-1/PD-L1 interaction in the tumor microenvironment, this work shifts it into a different light… we are going to start thinking about this differently now." The paper, entitled "Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response" and published in the journal Nature, is a collab- oration between Wei Guo, Ph.D., a professor of biology in the School of Arts and Sciences at UPenn, and Xiaowei Xu, M.D., Ph.D., a professor of pathology and laboratory medi- cine in the Perelman School of Medicine at UPenn. The researchers purified exosomes from a panel of human primary and metastatic melanoma cells lines by differential centrifugation, and analyzed the proteins associated with the exosomes by reverse phase protein array (RPPA) a large- scale antibody-based quantitative proteomics technology. PD-1, found on the surface of T cells, regulates the immune system's response to cells of the human body act- ing to inhibit T cells from attacking other cells in the body. However, when PD-1 is bound to PD-L1, the T–cell killing is inhibited. Tumor cells evade immune surveillance by upreg- ulating the surface expression of PD-L1—which, when bound to PD-1 on T cells, initiates the anticancer response (or immune checkpoint response). Checkpoint inhibitors block PD-1, reinvigorating the T cells, and opening up the attack on the cancer cells by the immune system. To look at the secretion of exosomal PD-L1 by melanoma cells in vivo, the researchers established human melanoma xenografts in nude mice. Human PD-L1 was identified on the circulating exosomes from mice bearing human mela- noma xenografts, but not the control mice. Not only did the level of circulating PD-L1+ exosomes correlate with tumor size, but adding PD-L1+ exosomes accelerated the progres- sion of melanoma tumors. In addition, the researchers found that the PD-L1+ exosomes inhibit the T cells. In essence, the tumors are releasing the exosomes to circu- late in the body via the bloodstream, to inhibit T cells before they reach the site of the tumor. Guo described it by say- ing, "essentially, exosomes secreted by melanoma cells are Immune-Evasion Mechanism May Help Explain the Differences in Responses to Immunotherapy By Julianna LeMieux, Ph.D. Exosomes Containing PD-L1 Could Predict Immunotherapy Responses Secretion of exosomes by tumor cells (lower right) to fight the T cells (up- per left). The labs of Wei Guo, Ph.D., and Xiaowei Xu, M.D., Ph.D., University of Pennsylvania (continued on next page) "This work opens the door to an important question as to whether circulating PD-L1+ exosomes could be a clinical predictor if they are correlated to patient outcomes." —James L. Gulley, M.D., Ph.D., National Cancer Institutes

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