胃・食道接合部・食道腺がんに対するレゴラフェニブ・ニボルマブ・化学療法の併用療法の効果と、治療への耐性が生じる機序を解明 ～新たな併用療法の治療成績を示すとともに、治療に伴う腫瘍免疫微小環境の変化と治療抵抗性に関わる仕組みの一端を明らかに～

2026-11-09 国立がん研究センター

図1　レゴラフェニブ、ニボルマブ、化学療法の併用療法による抗腫瘍効果

＜関連情報＞

• https://www.ncc.go.jp/jp/information/pr_release/2026/1109/index.html
• https://www.science.org/doi/10.1126/scitranslmed.aec7235

進行胃癌におけるレゴラフェニブ、ニボルマブ、および化学療法中の腫瘍免疫微小環境の経時的変化 Longitudinal remodeling of the tumor-immune microenvironment during regorafenib, nivolumab, and chemotherapy in advanced gastric cancer

Kota Itahashi, Akihito Kawazoe Tadayoshi Hashimoto, Yue Yan, Takuma Irie, Hiromi Ono, Hitomi Tamura, Kyoko Hongo, Takashi Ikeno, […] , and Kohei Shitara
Science Translational Medicine  Published:4 Nov 2026
DOI:https://doi.org/10.1126/scitranslmed.aec7235

Abstract

Previous studies combining the multikinase inhibitor regorafenib with a PD-1 inhibitor showed promising activity in gastric cancer. We conducted a phase 1b/2 trial (NCT05394740) of first-line regorafenib, nivolumab, and chemotherapy in 30 patients with mismatch repair–proficient gastric cancer and investigated its impact on the tumor microenvironment. The primary end point was met; 22 of 30 patients showed objective tumor response (73%; 80% confidence interval, 60.3 to 83.8). Single-cell RNA and T cell receptor sequencing were performed on biopsy samples at baseline, during treatment, and at disease progression. The combination treatment increased tumor antigen–reactive CD8⁺ T cells and M1-like proinflammatory macrophages and decreased immunosuppressive and tumor-promoting populations, including activated CCR8⁺ regulatory T cells, LRRC15⁺ cancer-associated fibroblasts (CAFs), RGS5⁺ pericytes, and APLN⁺ tip cells. At progression, LRRC15⁺ CAFs and APLN⁺ tip cells remained reduced, activated CCR8⁺ regulatory T cells reexpanded, and additional treatment-resistant subsets emerged, including APOC1⁺ lipid-associated macrophages. In murine models of acquired resistance, therapeutic targeting of these suppressive immune cell populations with antibodies against CCR8 or TREM2 in combination with PD-1 blockade restored antitumor immunity. These findings demonstrate dynamic remodeling of the tumor microenvironment and suggest potential therapeutic targets.