Although immunotherapies have provided beneficial results for patients in the treatment of various hematological and solid malignancies, they can cause severe adverse events that limit the benefits patients obtain from such treatments. The most frequent immune-related adverse event is colitis, an inflammatory toxicity that can lead oncologists to suspend treatment. A study by Lo et al. in Science addresses the mechanisms by which anti-CTLA-4 immunotherapeutic treatment leads to colitis in mouse models of cancer.

First, the authors established a mouse model of immunotherapy-induced colitis that does not need an additional intervention to induce inflammation, unlike current models. This was achieved by treating mice harboring a wild mouse gut microbiome with anti-CTLA-4 antibodies. Using this model, the authors showed that with anti-CTLA-4 treatment, remodeling of CD4+ T cell populations induced colitis in mice bearing tumors of colorectal cancer or melanoma. In particular, the authors observed that intestinal inflammation was caused by the activation of IFNγ-producing type 1 helper T cells, together with the depletion of a subset of RORγt-expressing regulatory T cells through interaction of the Fc domain of anti-CTLA-4 with Fcγ receptors. To overcome this toxicity, the authors developed anti-CTLA-4 nanobodies lacking the Fc domain that preserved anti-tumor immunity ability without inducing colitis.