LAUSR

Toxicity remains a major limitation of immune checkpoint blockade (ICB) in cancer treatment, and is likely to become increasingly problematic as treatment indications broaden and novel combinations progress. ICB-induced immunerelated adverse events (irAEs) in the clinic are predominantly managed as they are detected either biochemically or clinically, often requiring delay or cessation of treatment and use of immunosuppressive agents, and usually contributing to patient morbidity and, more rarely, mortality. A minimally invasive predictive biomarker for irAEs is a clinical priority but remains elusive. Biomarker research, however, has predominantly focused on predictive markers for treatment response (such as programmed death-ligand 1 [PD-L1] expression) and prognostic markers for disease trajectory (such as serum lactate dehydrogenase). IrAEs, including colitis, correlate with improved ICB response in most settings (e.g. Topalian et al.), with notable exceptions (such as Tiu et al.). Understanding the immune underpinning of irAEs then may not only improve treatment administration and patient care, but also provide insights into mechanisms of ICB-induced autoimmunity more broadly and lead to novel therapeutic targets. Furthermore, delineating shared versus distinct drivers of anticancer and antihost responses is a necessary first step to uncoupling ICB-induced anticancer response from toxicity; the “holy grail” of immunotherapy. The recently published article by Nahar et al. provides insight into immune changes associated with colitis, a common ICB-induced toxicity. Diarrhea or colitis occurs in up to 30% of patients treated with a combination of anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) and anti-PD-1 (programmed cell death protein 1), particularly contributed to by antiCTLA-4 (20% in monotherapy) and compounded by anti-PD-1 (7% in monotherapy). In this study, the authors explore the immune landscape of ICB-induced colitis by mass cytometry analysis of peripheral blood from recruited patients with melanoma treated with ICB, paired with analysis of endoscopic biopsies from inflamed and non-inflamed areas of the colon from patients with colitis (Figure 1a). Using unsupervised FLOWSOM clustering and manual gating strategies, Nahar et al. screened 45 cell surface proteins for unique intestinal and systemic immune changes associated with colitis before and after ICB (Figure 1b). Proliferating Ki-67 CD8 and CD4 T cells were expanded in the peripheral blood of both groups post-ICB treatment compared with pre-ICB treatment; however, the shift was more pronounced and reached statistical significance only in patients who developed colitis. CD4 and CD8 T cells and T regulatory cells were expanded within biopsies from endoscopically inflamed tissue in patients with colitis, but not within adjacent normal tissue. These findings support a recent study by Luoma et al. which also observed an increase in T-cell populations in ICB-induced active colitis bowel segments. Conversely, CD14 monocytes were elevated more broadly across inflamed and noninflamed intestinal tissue, as well as in peripheral blood at time of colitis onset and prior to treatment, suggesting that CD14 monocytes contribute to ICB-induced colitis and may have value as a predictive biomarker. The increase in peripheral blood and intestinal CD14 monocytes associated with ICB-induced colitis here draws parallels with immune phenotypes observed in primary inflammatory bowel disease (IBD), specifically active Crohn’s colitis, Correspondence Megan Barnet and Deborah L Burnett, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Road, Darlinghurst, NSW 2010, Australia. E-mails: [email protected] and [email protected]