Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

儿童中由种系 DNA 错配修复缺陷或聚合酶校对缺陷（MMRD 和 PPD）引起的癌症在人类中具有最高的突变和微卫星插入缺失（MS-indel）负担。MMRD 和 PPD 癌症通常是致命的，因为它们对化学辐射具有固有的抵抗力。尽管免疫检查点抑制剂 (ICI) 在之前的研究中未能使儿童受益，但我们假设 MMRD 和 PPD 引起的超突变将改善这些患者 ICI 治疗后的结果。使用国际联盟注册研究，我们报告了来自 38 名患者的 45 种进行性或复发性肿瘤的 ICI 治疗。在大多数患者中观察到持久的客观反应，最终达到 41.4% 的 3 年生存率。高突变负荷预测超高突变癌症的反应（> 每 Mb 100 个突变）富集 MMRD + PPD 组合，而 MS-indels 预测 MMRD 肿瘤的反应，突变负荷较低（每 Mb 10-100 个突变）。此外，即使在胶质瘤等“免疫冷”肿瘤中，这两种机制都与免疫浸润增加有关，有助于产生良好的反应。假性进展（耀斑）很常见，并且与肿瘤微环境和全身的免疫激活有关。此外，继续 ICI 治疗的发作患者获得了持久的反应。这项研究证明了以前未知对 ICI 治疗有反应的肿瘤患者的生存率提高，包括中枢神经系统和同步癌症，并确定了突变负荷和 MS-indels 在预测对免疫治疗的持续反应中的双重作用。