Project Summary
Immune checkpoint inhibitor therapy has drastically improved the prognosis of patients with several advanced-
stage cancers that were initially considered terminal. However, the increased use of checkpoint inhibitors has
resulted in the common emergence of immune-related adverse events (irAEs). Even though they are typically
excluded from clinical trials, in clinical practice, patients with autoimmune predisposition are offered checkpoint
inhibitors and have the greatest risk for developing irAEs. The mechanism driving this immune toxicity is poorly
understood, and even less is known about how checkpoint inhibitors interact with immune systems prone to
autoimmunity. Since malignancies are life-threatening diseases, there is an unmet medical need to decouple
autoimmune toxicities from checkpoint inhibitor antitumor response. I hypothesize that individuals can be
predisposed to irAEs based on a combination of their genetics and specific gut microbes. In this proposal,
I established a mouse model that reflects the emerging paradigm of autoimmune predisposition and the role of
the microbiome in the development of irAEs. I will use the Act1-/- mice, which develop spontaneous systemic
lupus erythematous and Sjogren-like autoimmune diseases in specific pathogen free conditions with elevated
baseline Th17 and B cell activity after aging. Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies
significantly expedited and exacerbated the onset and severity of autoimmune attack. In Aim 1, I will test the
hypothesis that B cells drive irAEs in Act1-/- mice while still maintaining checkpoint inhibitor efficacy. I also
determined that GF Act1-/- mice are not susceptible to irAE development, which aligns with the growing evidence
of the microbiome’s critical role in defining responsiveness to checkpoint inhibitors as well as the mitigation of
irAEs. In Aim 2, I will test the hypothesis that while ICI efficacy has been linked to certain members of the
intestinal microbiota community, a distinct subset of microbes can allow for the induction of irAEs in a genetically
susceptible host. The mechanisms studied in this proposal may prove useful for the foundation of a clinical
genetic screening approach for the patient population prior to ICI delivery.
