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Resistance to systemic immune checkpoint inhibition in the peritoneal niche
Daryl Kai Ann Chia1, Yong Xiang Gwee2, Raghav Sundar3,4,5,6,7
1Department of Surgery, University Surgical Cluster, National University Hospital, Singapore.
Abstract:
Immune checkpoint inhibition (ICI) is an established therapeutic option for patients with deficient mismatch repair or high levels of microsatellite instability tumors. Yet, response to ICI among this group is varied, with nearly one-third of patients exhibiting primary resistance. Initial efforts in studying mechanisms of resistance to ICI have focused on intrinsic tumor factors. Host factors such as metastatic niches have unique biological properties that may mediate resistance to ICI but have been less studied date. Patients with metastatic d-MMR/MSI-H gastrointestinal cancers and peritoneal metastases (PM) who had concurrent ascites have been recently shown to have worse outcomes with ICI therapy compared with patients with PM without ascites and patients with non-PM metastases. The juxtaposition of tumors with an intrinsic sensitivity to ICI failing to respond by virtue of the presence of ascites within the peritoneum, brings to the forefront the critical role of the metastatic niche. In this commentary, we discuss mechanisms for ICI resistance that may arise from the immunoprivileged state of the peritoneal cavity, paracrine factors within malignant ascites or tumor-peritoneum interactions. An improved understanding of the peritoneal microenvironment and the use of peritoneal-directed therapies may ameliorate the modest benefit of ICIs in this unique clinical entity.
Insights
Immune checkpoint inhibition (ICI) resistance is common in deficient mismatch repair (d-MMR) or microsatellite instability-high (MSI-H) tumors. The peritoneal metastatic niche, particularly with ascites, may drive this resistance, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Immunology
- Gastroenterology
Background:
- Immune checkpoint inhibition (ICI) shows efficacy in deficient mismatch repair (d-MMR) or high microsatellite instability (MSI-H) tumors.
- Primary resistance to ICI affects nearly one-third of eligible patients, with mechanisms often attributed to intrinsic tumor factors.
- Metastatic niches, particularly the peritoneal environment, are understudied as potential mediators of ICI resistance.
Discussion:
- Patients with metastatic d-MMR/MSI-H gastrointestinal cancers and peritoneal metastases (PM) with ascites exhibit worse outcomes with ICI therapy.
- The peritoneal cavity's immunoprivileged state, malignant ascites, and tumor-peritoneum interactions may contribute to ICI resistance.
- This highlights the critical role of the metastatic niche in modulating treatment response.
Key Insights:
- The presence of ascites in peritoneal metastases (PM) is associated with poorer ICI outcomes in d-MMR/MSI-H gastrointestinal cancers.
- Mechanisms of resistance may involve the peritoneal microenvironment's unique immunobiology.
- Tumor-peritoneum interactions and paracrine signaling within ascites are potential drivers of resistance.
Outlook:
- Further research into the peritoneal microenvironment is crucial for understanding ICI resistance.
- Development of peritoneal-directed therapies could enhance ICI efficacy in this patient population.
- Targeting niche-specific resistance mechanisms may improve outcomes for patients with advanced d-MMR/MSI-H cancers.
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