Perturbing and Reconstructing Immunity Hub Elements in Cancer

Immunotherapy has revolutionized cancer care, but most patients don’t respond to it and those who do frequently relapse. Currently, many immunotherapies focus on T cells because they can kill tumor cells. New technologies enable researchers to measure T cell encounters with other cells in the tumor microenvironment. These interactions likely alter T cell state and capacity to kill tumor. 

In his postdoctoral work, Dr. Chen described “immunity hubs,” which are multicellular structures present in multiple types of cancer, and which are putative centers of antitumor immune responses. These hubs are composed of activated T cells and myeloid cells, among other cell types, and  Dr. Chen is particularly interested in a subclass of immunity hubs which he terms stem-immunity hubs. These are immunity hubs that are enriched with stem-like invigorated T cells and the chemokine CCL19, one source of which may be a specialized tumor-associated fibroblast. Dr. Chen has already shown that these tumor immunity hubs are associated with favorable patient response to immunotherapy and has developed an imaging-based test using the presence of immunity hubs to predict immunotherapy response in non-small cell lung cancer (NSCLC.) Further, stem-immunity hubs and their CCL19+ fibroblasts seem to be particularly strongly associated with favorable immunotherapy results and progression free survival and may provide another avenue for leveraging immunotherapy.

Dr. Chen will use his Young Investigator Award to further his study of immunity hubs. First, he will use recently developed imaging technology to study and map immunity hubs, describing how their composition and organization associate with chemo-immunotherapy, with an eye toward new targets to overcome treatment resistance.  He will also investigate whether immunity hubs are related to “tertiary lymphoid structures,” another multicellular network that has been recently associated with positive immunotherapy outcomes.  Finally, focusing on his finding that stem-immunity hubs are enriched with the chemokine CCL19, Dr. Chen will investigate whether the presence of CCL19+ fibroblasts is one reason the immunity-hubs are so strongly associated with positive therapeutic outcomes, and he hopes to identify the pathways that create CCL19+ fibroblasts.  Together, these aims are intended to identify targets that will make immunotherapy more effective for more patients in potentially multiple types of cancer.