Dissecting cause and effect of immune related Adverse Events in a novel mouse model.

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B156
Abstract ID: 6008

Presenting Author:
DIPYAMAN PATRA , Postdoctoral Associate at UPMC Hillman Cancer Ctr.

Abstract:

Immunotherapies targeting the inhibitory receptors PD-1 & CTLA-4 have brought incredible success in cancer treatment. However, ~90% & ~70% of patients receiving anti-CTLA4 or anti-PD1 develop immune-related adverse events (irAEs). Additionally, the failure of treatment strategies to mitigate serious irAE symptoms while maintaining immunotherapy efficacy results in abrupt termination of immunotherapy and toxic fatalities. One major obstacle in this endeavor has been the poor understanding of immunopathology of irAEs due to lack of a preclinical mouse model. Thus, we sought to develop a mouse model that faithfully recapitulates the clinical phenotypes of cancer patient irAEs via diet mediated perturbation of gut microbiome. We subjected B6 mice consuming either regular diet (RD) or western diet (WD) to 3 weeks of anti-PD1 treatment. Mice fed WD developed several immune toxicities including inflammation of colon, skin, pancreas, small/large intestine, & orofacial region upon receiving anti-PD1, while mice fed RD developed no symptoms. The onset of irAE symptoms was directly proportional to length of WD exposure before anti-PD1 administration. In colon, irAE was associated with significantly increased infiltration of CD4⁺ T cells & dendritic cells and reduction of suppressive Tregs in epithelial layer. Taken together, we have generated a first of its kind irAEs mouse model which is simple yet effective in replicating the clinical symptoms of systemic irAEs in cancer patients.