Gastrointestinal cancers have attracted the attention of researchers due to their high incidence and mortality rates (1). In the advanced stage, although the chemotherapy and radiotherapy have managed to extend the lifespan of patients, the effectiveness remains rather limited.

Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm in many tumor types and improved survival in a subset of patients with advanced or metastatic cancers (2, 3). The prominent members of this class of agents include the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor, the anti-programmed cell death 1 (PD-1) agents, and the anti-programmed cell death-ligand 1 (PD-L1) agents (4, 5). Despite their clinical efficacy, ICIs can induce various immune-related adverse events (irAEs) which limit their use in many patients. ICIs may affect peripheral tolerance to autoantigens, resulting in autoantibody formation, which could be associated with irAEs in various organs (6). ICIs can also activate T-cells with subsequent production of pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor, which may result in excessive off-tumor inflammation and autoimmunity (7). The molecular and cellular mechanisms driving irAEs are poorly understood, as are the predisposing risk factors (8, 9). Out of concern that patients with underlying autoimmune diseases are at increased risk for developing severe irAEs, they have systematically been excluded from checkpoint inhibitor clinical trials (10).

Immune-related colitis (IRC), an intestinal toxic reaction mainly manifested by diarrhea and bloody stool, which is triggered by ICIs, is one of the most common adverse events associated with PD-1/PD-L1 inhibitor therapy (11, 12). IRC is a distinct clinical and pathologic entity but has many features resembling UC (13). The roles of PD-1/PD-L1 in UC are unclear. PD-1 and PD-L1 are expressed by the colonic epithelium, and surface expression of PD-1/PD-L1 is higher in UC patients, suggesting a potential regulatory function (14). Several meta-analyses have suggested retrospectively that ICIs are generally safe in patients with low active or untreated autoimmune diseases (15, 16). However, a multicenter retrospective study has indicated that patients with preexisting IBD who received immunotherapy have an increased risk of immune checkpoint inhibitors-related colitis (17). However, the generalizability of these conclusions is limited by constraints in patient numbers and disease heterogeneity. Given the heightened susceptibility of UC patients to various malignancies, some of which are indications for immunotherapy, a comprehensive understanding of the occurrence patterns and effect on treatment efficacy of IRC within the UC population is crucial (18, 19).

We present the characteristics and impact on outcomes of IRC in patients with gastrointestinal cancers and preexisting UC who received immunotherapy across multiple medical centers. To our knowledge, this is the first multicenter study to explore the relationship between IRC and prognosis in the preexisting UC population.

This is the largest multicenter study to date examining the risk of IRC and its relationship with clinical prognosis in gastrointestinal cancer patients with preexisting UC who received anti-PD-1 antibodies. The result indicate significantly higher incidence of IRC in preexisting UC patients compared to those without UC. Notably, higher rates of severe IRC was observed in pre-UC group, along with an increased frequency of symptom recurrence post-treatment. However, there were no fatalities directly attributable to IRC recorded.

Our findings diverge from previous reports of immunotherapy in patients with underlying UC. Previous analyses of patients with underlying autoimmune diseases only included a limited number of UC patients and offered scant data on UC histories and prior diagnostic evaluations (20, 21). A multicenter retrospective study has previously explored the risk of IRC in IBD, but it did not further examine the relationship between IRC and prognosis (17). We have provided substantially more clinical details of UC than those previously reported, thereby establishing a clearer relationship between IRC and prognosis in UC, reducing the impact of selection bias and the variability due to disease heterogeneity, and facilitating the application of our results to other clinical situations.

In Our study, people without a history of UC showed that IRC were connected with longer PFS or OS ( Supplementary Figures S1A, B ), in line with previous studies (6). Patients in the pre-UC group without IRC also exhibited improved PFS and OS compared to those without IRC in non-UC group, although statistical significance was not achieved. We hypothesized that this effect may be attributed to the relatively active immune system in pre-UC patients, potentially leading to a higher response rate following anti-PD-1 antibody treatment. This hypothesis was supported in pre-UC patients with mild IRC, as their PFS and OS prolongation was more pronounced. However, it is important to note that this advantage of OS did not increase with the aggravation of IRC in pre-UC patients. This might imply that pre-UC patients with severe IRC could benefit less from immunotherapy, even though they showed advantages in PFS. This seemingly contradictory phenomenon can be explained from the following two aspects: Firstly, the clinical management of severe IRC usually includes the use of corticosteroids or other immunosuppressants, and ICIs may be suspended or even permanently discontinued. Such intervention may lead to the suppression of the immune system’s anti-tumor function, thereby affecting the patient’s long-term survival. Secondly, severe IRC often presents with severe symptoms such as diarrhea and bloody stools, which may lead to a series of systemic complications such as electrolyte imbalance and anemia. These non-tumor-related complications may directly increase the risk of death for the patient.

Previous meta-analyses have demonstrated a positive association between IRC and favorable outcomes. While the incidence of IRC was higher in IBD, the increased response rate of immunotherapy suggested that the benefits in this population likely outweighed the risks (22). Nevertheless, our results indicated that this conclusion mentioned above may not be universally applicable to all patient types. The relatively active immune system observed in pre-UC patients may signify more effective tumor-killing effect. However, the presence of IRC could indicate more intense autoimmune damage, particularly in pre-UC patients with severe IRC. This delicate balance between antitumor effect and autoimmune damage should be carefully considered when using ICIs in pre-UC population. Furthermore, larger studies with substantial sample sizes are needed to assess the rationality of immunotherapy in patients with underlying UC (23).

In the pre-UC cohort, a considerable proportion of patients developed severe IRC and received corticosteroid treatment. Currently, there is still considerable controversy over whether corticosteroids affect the anti-tumor efficacy of ICIs. Although it is theoretically speculated that corticosteroids may inhibit T-cell function through multiple mechanisms and thereby interfere with the anti-tumor effect of ICIs, only a few studies support this hypothesis. Notably, the corticosteroid treatment regimens used in these studies were mostly high-dose and long-term, and they all had certain limitations. For instance, when patients received corticosteroids to treat irAEs, they often discontinued ICIs treatment at the same time. Therefore, it is still unclear whether the shortened survival period is due to the use of corticosteroids or the interruption of ICIs treatment. A study in 2019 indicated that the use of high-dose corticosteroids in combination with other anti-tumor treatments at baseline might have an adverse effect on patients’ survival time, while low-dose application or corticosteroids not used due to the tumor itself did not show a significant impact on patients’ prognosis (24). The NCCN guidelines also point out that the use of corticosteroids to treat irAEs does not negatively affect the treatment outcome of tumors, a view consistent with the majority of research results. In this study, for patients with severe IRC, the corticosteroid treatment adopted was all low-dose, and the dosage was gradually reduced and stopped in a timely manner after symptom relief, thereby minimizing the potential impact of corticosteroids. Furthermore, for patients with severe IRC, whether ICIs treatment should be discontinued, the NCCN guidelines recommend that for patients with severe IRC, the treatment with ICIs should be suspended and immunosuppressive therapy initiated. In this study, all patients with severe IRC had their ICIs treatment suspended. Although severe IRC usually requires a temporary suspension of ICIs, not all patients need to permanently discontinue treatment. In cases where ICIs were restarted after IRC remission, some patients did not experience IRC again, suggesting that after a careful individualized risk assessment, the use of ICIs can be resumed as appropriate. At present, there is no unified consensus on whether the timing of interruption of ICIs treatment will affect their anti-tumor efficacy. Theoretically, ICIs exert their anti-tumor effects by activating T cells, and this effect does not immediately disappear after drug withdrawal but gradually weakens over time. This view is also supported by clinical observations, where tumor volume continues to shrink or the disease remains stable after ICIs treatment is stopped. Therefore, we believe that a short interruption of ICIs treatment may not significantly affect the prognosis of patients, but if the interruption is too long, it may lead to a weakening of the anti-tumor effect.

This study found that patients with a history of UC are more prone to IRC. Therefore, it is of great significance to explore whether UC and IRC share certain underlying pathogenic mechanisms. In the diseased mucosa of UC patients, the proportion of helper T cells 17 (Th17) cells, which mainly secrete interleukin-17A (IL-17A), is significantly increased. As a pro-inflammatory factor, interleukin-6 (IL-6) promotes the differentiation of Th17 cells and induces the production of IL-17A, leading to intestinal mucosal damage and is considered a key link in the pathogenesis of UC. Previous studies have also shown that in the intestinal tissue samples of IRC patients, the levels of IL-6 and the proportion of Th17 cells are also elevated, which is consistent with our observations (25, 26). Therefore, we speculate that the IL-6-Th17 signaling pathway may play an important role in the pathogenesis of both UC and IRC. Additionally, we observed that in UC patients without IRC, the levels of IL-6 and IL-17A in their bodies were still slightly higher than those in the healthy patients, suggesting that the intestinal immune system of UC patients may be in a pre-activated state, which may explain why UC patients are more prone to IRC. Another T cell subtype - regulatory T (Treg) cells expressing PD-1/PD-L1, also plays a core role in maintaining intestinal immune homeostasis. Their compensatory upregulation is an important adaptive response in the chronic inflammatory microenvironment of UC (27). This upregulation essentially represents a negative feedback mechanism initiated by the host to suppress excessive immune activation. Notably, in the chronic inflammatory environment of UC patients, although the number of Tregs remains relatively stable, their function is significantly impaired, mainly manifested as downregulated CTLA-4 expression, reduced IL-10 secretion, and selective depletion of the Treg subset with high PD-1 expression. When the PD-1 pathway is blocked by inhibitors, the remaining Tregs will completely lose their immunosuppressive ability, leading to uncontrolled effector T cells and exacerbating the inflammatory response (28).

Furthermore, a study has shown that mice transplanted with the intestinal microbiota of UC patients had a significantly increased incidence of colitis after treatment with PD-1 inhibitors (29). This study, from the perspective of the interaction between the intestinal microbiota and the immune system, reveals the potential role of the intestinal microbiota in the co-pathogenesis of UC and IRC. Another report published in Nature pointed out that anti-TNF-α treatment can significantly improve IRC symptoms, and infliximab (a classic anti-TNF-α drug) is also one of the main drugs for treating UC at present (30). In summary, there are multiple commonalities in the pathogenesis and treatment strategies between UC and IRC, and these cross-factors may be an important reason why UC patients are more prone to IRC. Therefore, actively managing the underlying UC during immunotherapy and providing early intervention with IL-6 antibodies to patients with higher baseline IL-6 levels are of great significance for preventing severe IRC.

This study has several limitations. Firstly, due to the retrospective study design, there is a risk of selection bias and partial data loss. Secondly, although the sample size of this study is the largest in this field to date, it is still relatively limited, which restricts our further subgroup analysis. Thirdly, given that UC is usually an exclusion criterion in various immunotherapy clinical trials, the use of ICIs is entirely determined by the attending physician based on clinical judgment, lacking a unified medication standard. Fourth, there is currently no recognized diagnostic criterion to distinguish UC recurrence from IRC. Moreover, many advanced cancer patients are reluctant to undergo invasive procedures such as endoscopy or biopsy when experiencing intestinal symptoms. Therefore, accurately identifying IRC and differentiating it from other types of enteritis remains a significant challenge in clinical practice, a problem not only present in this study but also a common issue in this field. Fifth, this study involves multiple medical centers, and due to differences in diagnostic and treatment standards among institutions, especially in the absence of unified guidelines, it may have an impact on the study results. Sixth, patients with severe IRC often experience treatment interruption and the use of corticosteroids. Due to the limited sample size, we were unable to further evaluate and exclude the influence of these factors on prognosis. Seventh, this study included multiple anti-PD-1 antibodies. Different types of anti-PD-1 antibodies may introduce a certain degree of heterogeneity, which could potentially affect the research results. Due to the limited sample size, we were unable to conduct further subgroup analyses to explore their specific impacts.

In summary, our findings suggest that the preexisting UC increases the risk of IRC in patients treated with ICIs. Notably, patients with mild IRC show better tumor control and longer survival, while the survival benefit for those with severe IRC is not obvious. Additionally, the serum levels of IL-6 and IL-17A in IRC patients are significantly elevated. Therefore, for preexisting UC patients treated with ICIs: mild IRC may suggest a favorable prognosis, and being vigilant and effectively managing the occurrence of severe IRC is crucial for maximizing clinical benefits. Targeting the IL-6 pathway may be a potential new strategy for treating IRC in the future.