Mechanism-rooted therapeutic strategies for immune-related toxicities induced by checkpoint inhibitors

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PROJECT SUMMARY/ABSTRACT Although immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment, they are associated with life- or organ-threatening complications, termed immune-related adverse events (irAEs). Steroids, the first-line of treatment for irAEs, significantly abrogate the anti-tumor efficacy of ICIs; however, our knowledge of the mechanisms and signs that underpin the onset and progression of irAEs is very limited. Furthermore, commonality and individuality of altered immunity between irAEs have never been characterized. Our clinical and translational studies have revealed significant impact of combined ICI therapy (cytotoxic T lymphocyte- associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors) on the severity of arthritis-irAE, -colitis-irAE, and -pneumonitis-irAE compared to PD-1 inhibitor monotherapy. Notably, T helper (Th)17 cell signatures were significantly enhanced in arthritis-irAE synovial fluid, colitis-irAE colon, and pneumonitis-irAE bronchoalveolar lavage. In parallel, our lab has developed arthritis-irAE, colitis-irAE and pneumonitis-irAE murine models recapitulating patients’ clinical settings. Importantly, like in humans, Th17 cell signatures were enriched in the inflamed tissue of mice with ICI-induced arthritis (synovium), colitis (colon), and pneumonitis (lung) after combined ICI-therapy and correlated with irAE disease severity. Interestingly, arthritis-prone mice developed arthritis after receiving fecal microbial transplant (FMT) from combined ICI arthritis donor mice, notably with enhanced Th17 cell signatures. We also observed that blockade of Th17- related cytokines, interleukin (IL)-6 and tumor necrosis factor alpha (TNFα), may pinpoint irAE immunity while preserving/enhancing the anti-tumor efficacy of ICI therapy in humans and mice. Further understanding of mechanisms underlying irAEs may lead to identification of common and valid biomarkers predicting development and/or reflecting severity of irAEs as well as to new steps in their treatment. Therefore, we propose to uncover shared and distinct cellular/molecular mechanism(s) underpinning irAEs (arthritis- irAE, colitis-irAE, and pneumonitis-irAE) development as well as establish efficient therapeutic strategies. Here, in Aim 1, we will identify the cellular and molecular mechanisms and therapeutic targets by utilizing our novel preclinical murine models of irAEs including arthritis, colitis, and pneumonitis. In addition, cellular, phenotypic, and transcriptomic analysis of biospecimens from cancer patients with arthritis-irAE, colitis-irAE or pneumonitis-irAE will help to uncover common or unique immunopathogenesis mechanisms between different irAEs. In Aim 2, we will develop optimal strategies for treatment of irAEs while preserving anti-tumor immunity by utilizing melanoma tumor model in mice with irAEs. The implications from this work will be significant and will help to: 1) discover mechanisms universally or distinctively present in irAEs; 2) identify mechanistic biomarkers reflecting irAE disease activity; and most importantly, 3) develop a mechanism-rooted therapeutic strategy for irAEs without sacrificing anti-tumor immunity.