Sawada Kentaro, Yamashita Riu, Sakai Shunsuke A, Horasawa Satoshi, Yoshikawa Ayumu, Fujisawa Takao, Kadowaki Shigenori, Kato Ken, Ueno Makoto, Oki Eiji, Komatsu Yoshito, Chiyoda Tatsuyuki, Horita Yosuke, Yasui Hisateru, Denda Tadamichi, Satake Hironaga, Esaki Taito, Satoh Taroh, Takahashi Naoki, Yamazaki Kentaro, Matsuhashi Nobuhisa, Nishina Tomohiro, Takeda Hiroyuki, Ohtsubo Koushiro, Ohta Takashi, Tsuji Akihito, Goto Masahiro, Kato Takeshi, Bando Hideaki, Tsuchihara Katsuya, Nakamura Yoshiaki, Yoshino Takayuki
Department of Medical Oncology, Kushiro Rosai Hospital, Kushiro, Japan.
Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Cancer Res Commun. 2025 May 1;5(5):857-870. doi: 10.1158/2767-9764.CRC-24-0543.
Although the gut microbiome is associated with cancer development and progression, little is known about the effects of the gut microbiome landscape and the efficacy of immune checkpoint inhibitors (ICI) across cancer types. We investigated the association between the microbiome, clinical features, and ICI efficacy across cancer types in a large nationwide screening project for solid tumors. Among 2,180 patients with advanced solid tumors enrolled in the SCRUM-Japan MONSTAR-SCREEN between October 2019 and September 2021, in the chemotherapy-naïve cohort (n = 817), a high prevalence of oral bacteria was observed in patients using proton pump inhibitors (PPI) and those with upper gastrointestinal cancers, particularly postoperative patients with gastric or pancreatic cancer. Among patients treated with ICIs (n = 333), a high abundance of sequence variants in the gut microbiome was not significantly associated with ICI efficacy across cancer types (HR = 0.94; 95% confidence interval, 0.73-1.21). However, high oral bacteria in feces significantly correlated with a shorter progression-free survival compared with low oral bacteria (median, 4.34 vs. 6.97 months; HR = 1.38; 95% confidence interval, 1.07-1.78). Notably, in patients using PPIs, a higher proportion of oral bacteria influenced progression-free survival outcomes of ICI treatment (median, 3.15 vs. 2.04 months; P = 0.08), unlike in PPI nonusers (median, 7.13 vs. 5.55 months; P = 0.74). This study of the gut microbiome has unveiled significant insights into its landscape and potential impact on ICI efficacy. It highlights that the abundance of oral bacteria in feces may play a critical role in diminishing ICI efficacy among patients using PPIs.
As part of the MONSTAR-SCREEN, a prospective nationwide project for patients with solid tumors, we found that although gut microbiome diversity does not consistently predict ICI efficacy across cancer types, a high level of oral bacteria in the gut is linked to reduced ICI effectiveness, especially in patients using PPIs. These findings highlight the potential clinical impact of microbiome variations on cancer treatment outcomes.
尽管肠道微生物群与癌症的发生和发展相关，但对于肠道微生物群格局以及免疫检查点抑制剂（ICI）在不同癌症类型中的疗效影响，我们知之甚少。我们在一项针对实体瘤的全国性大型筛查项目中，研究了微生物群、临床特征与不同癌症类型中ICI疗效之间的关联。在2019年10月至2021年9月期间纳入SCRUM-日本MONSTAR-SCREEN的2180例晚期实体瘤患者中，在未接受过化疗的队列（n = 817）中，使用质子泵抑制剂（PPI）的患者以及患有上消化道癌症的患者，尤其是胃癌或胰腺癌术后患者，口腔细菌的患病率较高。在接受ICI治疗的患者（n = 333）中，肠道微生物群中序列变异的高丰度与不同癌症类型的ICI疗效无显著关联（风险比[HR] = 0.94；95%置信区间，0.73 - 1.21）。然而，与低口腔细菌相比，粪便中高口腔细菌与无进展生存期缩短显著相关（中位数，4.34个月对6.97个月；HR = 1.38；95%置信区间，1.07 - 1.78）。值得注意的是，在使用PPI的患者中，较高比例的口腔细菌影响了ICI治疗的无进展生存结果（中位数，3.15个月对2.04个月；P = 0.08），这与未使用PPI的患者不同（中位数，7.13个月对5.55个月；P = 0.74）。这项关于肠道微生物群的研究揭示了其格局以及对ICI疗效潜在影响的重要见解。它强调粪便中口腔细菌的丰度可能在降低使用PPI患者的ICI疗效中起关键作用。
作为MONSTAR-SCREEN的一部分，一项针对实体瘤患者的全国性前瞻性项目，我们发现尽管肠道微生物群多样性并不能始终预测不同癌症类型的ICI疗效，但肠道中高水平的口腔细菌与ICI有效性降低有关，尤其是在使用PPI的患者中。这些发现突出了微生物群变异对癌症治疗结果的潜在临床影响。
