Lifestyle-induced regulatory T cell fragility primes adverse events after immune checkpoint blockade
(1) Patra D (2) Wolfgang K (3) Ye C (4) Rigatti L (5) Ertwine K (6) Morder KM (7) Jana J (8) Baral I (9) Hurd D (10) Bossong K (11) Mullett S (12) Dou Y (13) Gelhaus S (14) Vignali DAA (15) Davar D (16) Cillo AR (17) Delgoffe GM (18) Overacre-Delgoffe AE
Patra et al. fed mice a low-fiber, high-fat Western diet (inducing dysbiosis and outgrowth of Akkermansia) and treated them with anti-PD-1 to obtain the lifestyle-induced susceptibility to immune-related adverse events (irAEs) mouse model, LISA. LISA recapitulated the ICB toxicity profile affecting many patients, and was influenced by known demographic factors. Cytotoxic tissue-resident memory CD8+ T cells (TRM) and Tregs were increased in affected tissues. Tregs were fragile, less suppressive, and secreted IFNγ. Treg-specific disruption of IFNγ production or signaling and dietary reversal reduced irAE severity, but not antitumor efficacy. Treg fragility and cytotoxic TRM were also present in human irColitis.
Contributed by Ute Burkhardt
(1) Patra D (2) Wolfgang K (3) Ye C (4) Rigatti L (5) Ertwine K (6) Morder KM (7) Jana J (8) Baral I (9) Hurd D (10) Bossong K (11) Mullett S (12) Dou Y (13) Gelhaus S (14) Vignali DAA (15) Davar D (16) Cillo AR (17) Delgoffe GM (18) Overacre-Delgoffe AE
Patra et al. fed mice a low-fiber, high-fat Western diet (inducing dysbiosis and outgrowth of Akkermansia) and treated them with anti-PD-1 to obtain the lifestyle-induced susceptibility to immune-related adverse events (irAEs) mouse model, LISA. LISA recapitulated the ICB toxicity profile affecting many patients, and was influenced by known demographic factors. Cytotoxic tissue-resident memory CD8+ T cells (TRM) and Tregs were increased in affected tissues. Tregs were fragile, less suppressive, and secreted IFNγ. Treg-specific disruption of IFNγ production or signaling and dietary reversal reduced irAE severity, but not antitumor efficacy. Treg fragility and cytotoxic TRM were also present in human irColitis.
Contributed by Ute Burkhardt
ABSTRACT: Immune checkpoint blockade has transformed cancer therapy, but immune-related adverse events (irAEs) remain a major, sometimes fatal, limitation, and the lack of robust preclinical models has hindered mechanistic insight. We present the lifestyle-induced susceptibility to irAEs (LISA) model, in which diet-driven metabolic and microbial alterations recreate human-like susceptibility to anti-PD-1 toxicity. LISA recapitulates multi-organ irAEs with immune infiltration and cytokine production, severity depending on sex, age, treatment modality, and immunotherapy response. Mechanistically, dysbiosis marked by Akkermansia muciniphila enrichment accompanies aberrant immune activation, driving regulatory T cell (Treg) fragility and CD8+ cytotoxic effector populations, both observed in patients with irColitis. Dietary reversal, metabolite supplementation, and blocking interferon (IFN)-γ production or signaling in Tregs restored Treg stability and resolved inflammation. Human-to-mouse fecal microbiome transfer interacts with recipient diet to shape susceptibility. Together, these findings identify dietary, microbial, and immune drivers of irAEs, which can be leveraged to improve immunotherapy responses while minimizing toxicity.
Author Info:
(1) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment
Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (2) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (3) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) Division of Laboratory Animal Resources, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (5) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (6) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (7) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (9) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (10) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (11) Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15213, USA. (12) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Cellular and Molecular Pathology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (13) Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15213, USA. (14) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (15) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (16) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Center for Systems Immunology, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15206, USA. (17) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (18) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. Electronic address: overacre@pitt.edu.
