Abstract
Immune checkpoint blockade (ICB) immunotherapy increases antitumor immunity by blocking cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and displays robust clinical responses in various cancers. However, ICB immunotherapy also triggers severe inflammatory side effects, known as immune-related adverse effects (irAEs). One of the most common toxicities is immune checkpoint blockade-associated colitis (ICB associated colitis). The exact mechanism of ICB associated colitis remains to be explored. Here, we combined ICB (anti–CTLA-4 and anti-PD-1) treatment with a standard colitis model, in which a more severe form of colitis is induced in mice, to recapitulate the clinical observations in patients receiving combined ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy, during which colitis is the most frequent complication encountered. We found that the composition of the gut microbiota changed in ICB associated colitis. Principal component analysis of the gut microbiome showed an obvious reduction in the abundance of Lactobacillus in severe ICB associated colitis. Lactobacillus depletion completely by vancomycin augmented the immunopathology of ICB. Furthermore, we found that the ICB toxicity could be totally eliminated via the administration of a widely available probiotic Lactobacillus reuteri (L.reuteri). Oral administration of L. reuteri therapeutically inhibited the development and progression of colitis, thus ameliorating the loss of body weight and inflammatory status induced by ICB treatment. Mechanistically, the protective effect of L. reuteri was associated with a decrease in the distribution of group 3 innate lymphocytes (ILC3s) induced by ICB associated colitis. In conclusion, our study highlights the immunomodulatory mechanism of the gut microbiota and suggests that manipulating the gut microbiota by administrating L. reuteri can mitigate the autoimmunity induced by ICB, thus allowing ICB immunotherapy to stimulate the desired immune response without an apparent immunopathology.
Highlights
Immune checkpoint blockade (ICB) immunotherapy targeting intrinsic downregulators of immunity, such as cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) has shown durable clinical responses and recently been a source of promising new cancer treatments [1, 2]
While ICB immunotherapy stimulates T-cell activation and effective antitumor immune responses, it can have serious inflammatory side effects in some patients, known as immunerelated adverse effects, which resemble autoimmune disease [3]. irAEs are frequent and might occur in up to 90% of patients treated with the anti-CTLA-4 antibody [4] and in 70% of patients treated with a PD-1/PD-L1 antibody [5]
Despite achieving great clinical success, ICB immunotherapy as a monotherapy or as a part of various combinational strategies has challenges and limitations including the development of irAEs
Summary
Immune checkpoint blockade (ICB) immunotherapy targeting intrinsic downregulators of immunity, such as cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1) has shown durable clinical responses and recently been a source of promising new cancer treatments [1, 2]. Several immune-checkpoint-blocking mAbs have been approved for the treatment of patients with several types of cancer, and more and more patients will benefit from ICB immunotherapy in the months and years ahead. While ICB immunotherapy stimulates T-cell activation and effective antitumor immune responses, it can have serious inflammatory side effects in some patients, known as immunerelated adverse effects (irAEs), which resemble autoimmune disease [3]. Several reports from cohorts of ICB-treated patients suffering from colitis have confirmed the similarities between ICBassociated colitis and IBD both clinically and endoscopically [8]. Uncovering the mechanisms involved in its pathogenesis will greatly enhance our understanding and therapeutic management of ICB-mediated colitis
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