Department of Surgery, University Surgical Cluster, National University Hospital, Singapore.
Department of Haematology-Oncology, National University Cancer Institute, Singapore.
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004749.
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.
免疫检查点抑制（ICI）是一种针对错配修复缺陷或微卫星不稳定高肿瘤患者的既定治疗选择。然而，这组患者对 ICI 的反应各不相同，近三分之一的患者表现出原发性耐药。最初研究 ICI 耐药机制的努力集中在内在肿瘤因素上。宿主因素，如转移性小生境，具有独特的生物学特性，可能介导对 ICI 的耐药性，但研究较少。最近发现，患有转移性 d-MMR/MSI-H 胃肠道癌和腹膜转移（PM）并伴有腹水的患者与无腹水的 PM 患者和非 PM 转移患者相比，接受 ICI 治疗的预后更差。由于腹膜腔内存在腹水，对 ICI 固有敏感性的肿瘤未能响应，这凸显了转移性小生境的关键作用。在这篇评论中，我们讨论了可能源于腹腔免疫特权状态、恶性腹水中的旁分泌因子或肿瘤-腹膜相互作用的 ICI 耐药机制。对腹膜微环境的更好理解和使用腹膜导向治疗可能会改善 ICI 在这种独特临床实体中的适度获益。
