2024 Mentored Investigator Grant Recipient — MacLean Sellars, MD
MacLean Sellars, MD
Dana Farber Cancer Institute
Expanding the Antigen Landscape in High Grade Serous Ovarian Cancer
Project Summary
Immune surveillance and killing of cancer cells relies on T cell recognition of short, cancer specific protein sequences (antigens) on the surface of cancer cells. A major obstacle to immunotherapies in ovarian cancer — there are none approved — is the low number of antigens we are able to identify. Indeed, conventional antigen identification algorithms examine only small mutations in known genes; by this measure, ovarian cancer has few mutations relative to other cancers. I propose to expand the antigen landscape in ovarian cancer by identifying non-canonical antigens, derived from 1) the large scale genomic structural variations (genomic rearrangements, deletions, amplifications, etc) that define ovarian cancer and 2) non-canonical antigens made from previously unannotated proteins. I will use deep sequencing of the RNA and DNA of patient derived tumor organoids to identify genomic structural variants that may give rise to novel antigens. I will use ribosome profiling in these same organoids to identify potential non-canonical proteins. I will use mass spectrometry to identify which of these non-canonical antigens are present on the surface of patient tumor-derived organoids. Finally, I will demonstrate that these non-canonical antigens are recognized by T cells from healthy donors and from ovarian cancer patients on a phase I cancer vaccine trial. This work will provide the basis for new vaccine and cellular immunotherapy targets.
This grant was made possible by generous donation from Li-An Yeh
Bio
Dr. MacLean Sellars is a medical oncology fellow in the Division of Gynecologic Oncology at the Dana Farber Cancer Institute, as well as a postdoctoral researcher in the laboratory of Dr. Catherine Wu. MacLean grew up in southern California, before majoring in Biology and Sociology at Haverford College. He went on to receive a PhD in Molecular Biology at the University of Strasbourg, France, where he studied mechanisms of lymphocyte activation and B cell class switch recombination in the laboratory of Drs. Susan Chan and Philippe Kastner. Following his graduate studies he embarked on a post doctoral fellowship in the laboratory of Dan Littman (HHMI/NYU), using T cell development as a model system to understand the epigenetic regulation of cell fate decisions. During this post-doc, his mother’s life was cut short by advanced uterine cancer, which inspired him to pursue medicine and eventually medical oncology. He completed his MD at the David Geffen School of Medicine and his residency in internal medicine at the Massachusetts General Hospital, before starting his fellowship in at the Dana Farber Cancer Institute. He is interested in understanding how the immune system recognizes ovarian cancers, and how we can improve immune targeting in ovarian cancer.