帕博利珠单抗联合二甲双胍治疗转移性头颈部癌的 II 期可行性研究
A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.
二甲双胍联合帕博利珠单抗耐受性良好，仅出现轻度胃肠道不良事件，并展现出有前景的活性，值得在随机试验中进一步研究。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
ABCB11 在未成熟三级淋巴结构中积累，参与外源物代谢过程，并预测头颈部鳞状细胞癌对 PD-1/PD-L1 抑制剂的耐药性
英文原题：ABCB11 accumulated in immature tertiary lymphoid structures participates in xenobiotic metabolic process and predicts resistance to PD-1/PD-L1 inhibitors in head and neck squamous cell carcinoma.
查看英文原题
ABCB11 accumulated in immature tertiary lymphoid structures participates in xenobiotic metabolic process and predicts resistance to PD-1/PD-L1 inhibitors in head and neck squamous cell carcinoma.
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中文摘要
近几十年来，头颈部鳞状细胞癌（HNSCC）复发风险较高，多模式治疗也未能显著改善生存。免疫检查点抑制剂（ICI）对少数HNSCC患者有效，但多数患者无应答。
本研究首次揭示，异生物代谢过程与HNSCC对程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）抑制剂耐药显著相关；同时发现，未成熟三级淋巴结构（TLS）中ABCB11积累可预测PD-1/PD-L1抑制剂治疗后较差的无进展生存期（PFS）和总生存期（OS）。
此外，在HNSCC组织中，与CD45⁺ABCB11⁻TIL（肿瘤浸润淋巴细胞）相比，CD45⁺ABCB11⁺ TIL中参与异生物代谢的细胞色素P450 1A2（CYP1A2）表达显著上调。对110份HNSCC组织进行全切片扫描，并开展苏木精-伊红和多光谱免疫荧光（mIF）染色，结果显示ABCB11在未成熟TLS中与CYP1A2高度共表达；ABCB11与CYP1A2在未成熟TLS中的共定位显著关联免疫抑制性调节性T细胞（Treg）浸润升高。
本研究揭示，未成熟TLS中ABCB11积累可能上调CYP1A2、介导异生物代谢，进而增加免疫抑制性Treg浸润并诱导HNSCC对PD-1/PD-L1抑制剂耐药。
展开英文摘要原文
Head and neck squamous cell carcinomas (HNSCC) are at a high risk of recurrence and multimodal therapy have not significantly improved survival in recent decades. Although immune checkpoint inhibitors (ICIs) are effective in a small proportion of HNSCC patients, the majority do not respond.
In this study, we for the first time revealed that xenobiotic metabolic process was significantly associated with resistance to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors in HNSCC and found that ATP binding cassette subfamily B member 11 (ABCB11) accumulated in immature tertiary lymphoid structures (TLSs) predicted worse progression-free survival (PFS) and overall survival (OS) after PD-1/PD-L1 inhibitors therapy.
Moreover, the expression of cytochrome P450 1A2 (CYP1A2), a cytochrome P450 (CYP) enzyme that participates in xenobiotic metabolic process, was significantly upregulated in CD45 + ABCB11 + tumor-infiltrating lymphocytes (TILs) compared with CD45 + ABCB11 - TILs in HNSCC tissues.
Whole slide scans of 110 HNSCC tissues with hematoxylin-eosin (HE) and multispectral immuno-fluorescent (mIF) staining revealed that ABCB11 had a high co-expression with CYP1A2 in immature TLSs, and colocalization of ABCB11 and CYP1A2 in immature TLs significantly associated with high infiltration of immunosuppressive T-regulatory (Treg).
Our study revealed that ABCB11 accumulated in immature TLSs might upregulate CYP1A2 to mediate xenobiotic metabolic process, thus increase the immunosuppressive Treg infiltration, and induce resistance to PD-1/PD-L1 inhibitors in HNSCC.
论文信息
- 作者
- Ning J、Hao J、Guo F、Hou X、Li L、Wang J、Wang S、Gao Y
- 第一作者单位
- Department of Thyroid and Breast Surgery, Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin 300121, China; Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.China
- 通讯作者单位
- Department of Thyroid and Breast Surgery, Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin 300121, China; Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. Electronic address: headandneck2008@126.com.China
- 期刊
- Translational oncology2023 Oct
- 原文标识
- PubMed 37517143 · DOI 10.1016/j.tranon.2023.101747
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