Session 13 – Advances in Cancer Immunotherapy
Date: 24 July (Friday) 14:00 – 15:30 (GMT+8)
Venue: 701EF, 7F, TaiNEX2 / Online event platform
Professor Mark Smyth (FAA, FAHMS) is a Senior Scientist and Immunology Coordinator at QIMR Berghofer Medical Research Institute. He completed his PhD in 1988 and trained at the NCI (1988-1992), before commencing his independent research career in Australia. Over the last 20 years he rekindled world-wide interest in cancer immune surveillance, defined immune-mediated dormancy of cancer, and the role of the host immunity in chemotherapy and targeted therapy responses. More recently, he has provided new means of classifying natural killer cell (NK) subtypes and three new targets for cancer immunotherapy. He is a past winner of the William Coley Medal and Charles Brupbacher Foundation Prizes in Cancer Research. He has a number of scientific research agreements, consultancies, new patents and other patents licenced to industry. He has an H-Index of 157, is the highest cited immunologist in Australia, and is a Senior Editor, and Advisory Board Member for Cancer Discovery and Science, respectively.
Speech title & Synopsis
Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PD-L1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy. This is the first study to demonstrate that high tumor CD155 expression affects response to anti-PD1 therapy in metastatic melanoma patients. While the upregulation of inhibitory molecules is a major driver of immune escape in cancer, less is known about the regulation of T cell activating receptors within the tumor microenvironment. Here, we describe that tumor-derived CD155 contributes to the downregulation and degradation of the activating receptor CD226 (DNAM-1) in mouse and human CD8+ T cells, leading to profound loss of effector function and cancer immune evasion. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells significantly correlated with improved progression free survival following immune checkpoint blockade therapy. In summary, we discovered a new immune escape mechanism in which tumor cells inhibit T cells through targeted downregulation and degradation of an activating receptor.