Researchers at The University of Texas MD Anderson Cancer Center have identified a previously unrecognized role for B cells in triggering and sustaining immune checkpoint inhibitor (ICI)-related colitis, providing new insights into how this potentially serious immune-related adverse event develops. The study, published in Cell Reports, found that alterations in circulating B-cell number and activity could be detected before the onset of clinical symptoms, raising the possibility that B-cell profiles could eventually help identify patients at increased risk of ICI-related colitis.
Immune checkpoint inhibitors have transformed the treatment of several cancers by releasing inhibitory pathways that restrain antitumor immune responses. However, the same immune activation can result in inflammatory toxicities affecting normal tissues. ICI-related colitis is an important gastrointestinal immune-related adverse event that can cause diarrhea, abdominal pain and, in more severe cases, gastrointestinal bleeding. Although clinical management strategies are available, predicting which patients will develop colitis before symptoms appear remains challenging.
The new study, led by Roza Nurieva, PhD, Professor of Immunology at MD Anderson, investigated the immunological events that precede the development of ICI-related colitis. The researchers analyzed patient samples alongside preclinical models to determine whether specific immune-cell changes occurred before overt intestinal inflammation. The study was published online in September 2026 and included investigators from MD Anderson, Cleveland Clinic and other collaborating institutions.
The researchers found that patients susceptible to ICI-related colitis had increased numbers and activity of circulating B cells during an asymptomatic stage. Notably, the altered B-cell population included cells expressing markers associated with migration to the gut, antigen presentation and production of proinflammatory cytokines. Similar changes were observed in mice susceptible to ICI-induced colitis. These findings suggested that B-cell abnormalities may emerge before the inflammatory response becomes clinically apparent.
The temporal sequence of the immune response was particularly important. Altered B-cell activity was detected before the characteristic intestinal T-cell responses associated with ICI-related colitis. This observation raised the possibility that B cells are not merely responding to established intestinal inflammation but may participate in initiating the inflammatory cascade that subsequently involves pathogenic T cells.
The investigators then examined whether B cells were functionally required for development of colitis. In preclinical experiments, depletion of B cells before ICI administration prevented the development of ICI-related colitis and reduced the accumulation of pathogenic T cells in the intestine. The findings provide experimental evidence that B cells can act upstream of the T-cell response and contribute to the development of intestinal inflammation following checkpoint blockade.
The study also pointed to a possible role for the gut microbiome. Susceptible preclinical models showed evidence of latent microbial dysbiosis together with abnormal B-cell activity before ICI treatment. This raised the possibility that alterations in the intestinal microbial environment may influence B-cell function and create a state of susceptibility that becomes clinically evident after immune checkpoint blockade.
Further experiments using fecal microbiota transplantation (FMT) provided additional support for this connection. Restoring a healthier microbial composition reduced the severity of colitis and associated inflammation in the preclinical models. The findings suggest that interactions between the gut microbiome and B-cell responses may be an important component of the biological pathway leading to ICI-related colitis.
Together, the findings support a model in which subclinical alterations in the gut environment are associated with abnormal B-cell activity before ICI treatment. Following checkpoint blockade, these B cells may promote the recruitment and activation of inflammatory immune cells and contribute to the emergence of pathogenic intestinal T-cell responses, ultimately resulting in symptomatic colitis.
The findings could have implications for the development of biomarkers for immune-related adverse events. Because changes in circulating B cells were detectable before clinical manifestations, blood-based assessment of B-cell number or function could potentially be investigated as a way of identifying patients at higher risk of ICI-related colitis. Such an approach could, if validated, allow closer clinical monitoring of susceptible patients during immunotherapy.
The results also raise the possibility of preventive strategies directed at B cells or the gut microbiome. However, these approaches remain investigational. B cells have important roles in normal immune function, while gut microbiota-based interventions can have complex and variable effects. Moreover, any strategy that suppresses or alters immune responses during cancer treatment would need to preserve the antitumor activity of checkpoint inhibitors.
The researchers therefore emphasize the need for further validation in larger patient cohorts. Future studies will need to determine which specific B-cell populations or functional characteristics provide the most reliable prediction of colitis, whether these changes can be detected consistently before symptoms develop, and whether targeting B-cell pathways or the gut microbiome can reduce toxicity without compromising cancer control.
The study adds B cells to the emerging picture of ICI-related colitis as a complex, multicellular process involving interactions among the immune system, intestinal environment and gut microbiome. Rather than representing a response that begins only after intestinal injury has occurred, the disease may involve measurable immune alterations during an earlier, clinically silent phase. Identifying these changes could ultimately provide new opportunities for predicting and managing one of the important complications of cancer immunotherapy.
Reference
- Turner N, Keam S, Abdel-Wahab N, Colunga-Minutti J, Trejo CA, Kugeratski FG, et al. B cell-guided inflammatory cascade perpetuates ICI-mediated colitis. Cell Rep. 2026;45(9):117969. doi:10.1016/j.celrep.2026.117969.