Immune checkpoint inhibitors (ICIs) have demonstrated improved survival rates over traditional chemotherapy for a variety of advanced-stage malignancies [1]. Under normal physiologic conditions, the activity of the immune system is regulated by a balance of T-cell activation and tolerance. This balance is mediated by a complex interaction between T-cell receptors and additional signaling molecules. Interactions with cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) receptor or the programmed cell death protein 1 receptor (PD-1) or ligand (PD-L1) negatively regulate T-cell activation and enable tumor evasion from immune detection. Several available monoclonal antibody drugs bind and block these molecules, causing upregulated immune activity and an anti-tumor response [1].

The immune-mediated actions of ICI are not limited to a tumor-related immune response. Increased immune activity can lead to off-target effects in other tissues and organs and produce immune-related adverse events (irAEs) [2]. Gastrointestinal toxic effects are among the most common irAEs, particularly enterocolitis, hepatitis, and pancreatitis [2, 3]. Enterocolitis is the most studied gastrointestinal irAE [4–10]. However, the literature on acute cholecystitis following ICI therapy includes only a few case studies: one due to nivolumab (anti–PD-1) and the other due to avelumab (anti–PD-L1) [11, 12]. Moreover, current treatment guidelines regarding irAEs do not comment on cholecystitis [13–16]. Expanding this knowledge is essential, as the use of immunotherapy is forecasted to increase, and there are several mechanisms that could increase the likelihood of gallbladder inflammation in patients receiving ICI: [1] the presence of liver metastasis with the potential for biliary obstruction, [2] rapid weight loss, which may enhance gallstone formation, [3] altered immunity with potentially increased susceptibility to infections, and [4] risk factors including advanced age, obesity, smoking, and high-fat diet.

The purpose of this study was to facilitate the identification and management of ICI-related cholecystitis, by expanding current knowledge about the clinical features and outcomes, to prevent devastating consequences and sustain ICI therapy.

ICIs are a promising cancer therapy but can lead to irAEs, which can affect any organ, owing to the nonspecific immune upregulation mediated by ICIs. To date, only two cases of ICI-related cholecystitis have been reported [11, 12]. Our case series represents the largest study to date of cancer patients on immunotherapy who developed cholecystitis.

Cholecystitis after ICI therapy is rare, occurring in only 0.6% of patients. This rate was higher than that of patients with corresponding cancer types who received non-ICI therapy (0.2%). We found that cholecystitis occurred significantly more frequently among anti–CTLA-4 recipients than among patients receiving other ICIs (P = 0.006), and this trend is similar to that among other irAEs [2]. However, the causality of cholecystitis cannot be attributed to ICI without microscopic confirmation. Hence, future research efforts should focus on establishing the etiology of cholecystitis in relation to ICI therapy. In our cohort, cholecystitis requiring invasive intervention (grade 3 or higher) was seen in 11 patients. In previous reports of ICI-related cholecystitis, only one study has detailed a case of complicated cholecystitis, in which the patient developed sepsis from cholangitis with cholecystitis [11]. In our cohort, six patients had complicated cholecystitis, including sepsis and gallbladder perforation. The incidence of complicated cholecystitis was higher with combination ICI therapy than with ICI monotherapy, which aligns with observations in other studies that increasingly severe irAEs are seen with combination ICI therapy [2].

Our study has many strengths: It is the largest to date of patients with various malignancies who developed cholecystitis after ICI therapy, and it adds to the body of evidence regarding irAEs. It highlights the importance of considering this rare adverse event among differential diagnoses in patients treated with ICIs: resumption of ICI therapy was associated with improved survival in our study. Yet, less than half of our cohort was able to resume ICI therapy following cholecystitis. Thus, the early recognition and appropriate management of ICI-related cholecystitis is vital. The findings of this case series also suggest that traditional management of cholecystitis is appropriate for ICI-related cholecystitis. The role of steroid in the management of ICI-related cholecystitis was unclear in this study.

Patients with malignancy have an increased risk of cholecystitis because they often have multiple risk factors for acute cholecystitis [18, 19]. In our study, many patients had known cholecystitis risk factors, including obesity, smoking, and advanced age. Also, four patients received ICI in combination with a chemotherapy agent known to cause cholecystitis, such as azacitidine. Interestingly, in our cohort, most patients had hematological or genitourinary malignancies despite that majority of patients receiving ICI in the original cohort are melanoma patients. This observation can be explained by the impaired immunity and the use of myelosuppressive therapy in patients with hematological malignancies, where both have been shown to be associated with increased risk of acute cholecystitis [19, 20]. In patients with genitourinary cancers, the frequent metastasis from renal cell carcinoma as well as the use of sorafenib and sunitinib in these patients have been linked with a higher risk of acute cholecystitis [18, 21–23].

The median time to onset of cholecystitis in our study (6 months) was longer than the generally reported timespan of 12 weeks for irAE onset; however, the first onset of irAEs can also occur as long as 1 year after discontinuation of therapy [16]. The clinical presentation of ICI-related cholecystitis was similar to that of traditional acute cholecystitis and included fever, right upper quadrant abdominal pain, nausea, vomiting, diarrhea, leukocytosis, and, for some patients, a positive infectious workup. Some patients had cholecystitis with atypical clinical symptoms but positive imaging findings. Many patients had modest elevations in liver transaminases and had cholestatic laboratory changes, in concordance with case reports [24]. These reports also documented a long latency—4-5 months until cholecystitis onset—which was reflected in our study.

Owing to the rarity of this entity and the current lack of evidence, there is no specific recommendation for management of ICI-related cholecystitis. The general consensus for any irAE recommends supportive care and immunotherapy continuity for mild toxicity and corticosteroids and halting immunotherapy for more severe toxicity. However, corticosteroid therapy is not part of the traditional approach for acute cholecystitis. In our study, patients who received systemic steroids, on the basis of general guidelines for irAEs, had worse overall survival, possibly because of a counter-effect of steroids on ICI therapy. However, we could not delineate the effect of steroid in this study because of the small number of patients receiving steroid and the various possible confounding factors for poor survival rate in these patients, especially being a poor surgical candidate due to impaired functional status and comorbidities. Because the pathogenesis of this form of cholecystitis is presumed to be immune mediated, the potential effect of steroids on survival needs to be clarified in a large-scale study to evaluate whether current treatments for irAEs in general can be appropriate for ICI-related cholecystitis. Future prospective studies validating our findings and investigating the role of steroids in the management of ICI-related cholecystitis are needed.

Despite the strengths of this study, some limitations should be acknowledged. The retrospective design limited the accuracy of the data collection. Second, as MD Anderson is a tertiary care center, some patients were diagnosed and received treatment for cholecystitis at an outside institution. Third, as there are no established guidelines for ICI-related cholecystitis management, many patients who were hospitalized for suspected cholecystitis were treated at the discretion of the treating physician. Fourth, we did not include microscopic examination to delineate the causality of cholecystitis by ICI, and therefore, the association between ICI and cholecystitis still needs to be verified. Last, this study was a case series with a small sample size that did not allow us to perform advanced statistical analysis.

ICI-related cholecystitis usually presents in a similar fashion to traditional acute cholecystitis and can complicate ICI treatment, leading to its interruption. Our study represents the largest compilation of data regarding this rare entity, which appears to occur more frequently after anti–CTLA-4 therapy compared with other ICI agents. The rate of ICI-related acalculous cholecystitis was higher than that of patients receiving other non-ICI chemotherapy. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear. Clinicians need to be aware of adverse events occurring with ICI use, especially because prompt diagnosis and treatment of these adverse events allow continuation of ICI therapy. Of note, given the lack of response of cholecystitis to steroids, large prospective studies are needed to investigate cholecystitis in relation to ICI therapy and to provide healthcare professionals with evidence-based data for its management.