免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
抑制微粒体前列腺素 E2 合酶可减少黑色素瘤肿瘤中的胶原沉积，并可能通过减少 T 细胞耗竭来提高免疫治疗疗效
英文原题：Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion.
查看英文原题
Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion.
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中文摘要
花生四烯酸通路参与多种癌症中的免疫抑制。我们此前发现，位于环氧合酶2（COX-2）下游的微粒体前列腺素E₂合酶1（mPGES-1）会限制黑色素瘤抗肿瘤免疫；此外，遗传性去除mPGES-1可特异性增强免疫检查点阻断疗法。本研究旨在区分mPGES-1与COX-2在肿瘤免疫中的作用，并评估mPGES-1抑制剂增强黑色素瘤免疫治疗的潜力。遗传敲除mPGES-1与敲除COX-2导致的前列腺素代谢物谱不同。在同基因小鼠模型中，mPGES-1缺陷细胞与COX-2缺陷细胞的致瘤性相似，尽管去除mPGES-1对抑制PGE₂合成的作用较弱，这提示可能存在PGE₂以外调节肿瘤免疫的因子。RNA测序分析显示，去除mPGES-1可降低胶原相关基因表达，这些基因与免疫抑制特征相关。在小鼠模型中，mPGES-1缺陷肿瘤的胶原减少；TIL（肿瘤浸润淋巴细胞）表型分析显示，与COX-2缺陷肿瘤相比，mPGES-1缺陷肿瘤中TIM3⁺耗竭CD8⁺ T细胞更少。mPGES-1抑制剂CAY10678增强抗PD-1治疗的效果，与选择性COX-2抑制剂塞来昔布相当。本研究表明，mPGES-1抑制剂通过减少胶原沉积和T细胞耗竭，可能成为增强黑色素瘤免疫治疗的有前景辅助药物。 意义：胶原是细胞外基质的主要成分，可能影响癌症进展中的肿瘤免疫微环境。本文显示mPGES-1在调节肿瘤免疫方面具有特异作用，与多种胶原相关基因相联系，并提出药理抑制mPGES-1可能有助于改善免疫检查点疗法。
展开英文摘要原文
UNLABELLED: The arachidonic acid pathway participates in immunosuppression in various types of cancer.
Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion.
In our syngeneic mouse model, mPGES-1-deficient cells exhibited similar tumorigenicity to that of COX-2-deficient cells, despite a lower ability to suppress PGE2 synthesis by mPGES-1 depletion, indicating the presence of factors other than PGE2 that are likely to regulate tumor immunity. RNA-sequencing analysis revealed that mPGES-1 depletion reduced the expressions of collagen-related genes, which have been found to be associated with immunosuppressive signatures.
In our mouse model, collagen was reduced in mPGES-1-deficient tumors, and phenotypic analysis of tumor-infiltrating lymphocytes indicated that mPGES-1-deficient tumors had fewer TIM3 + exhausted CD8 + T cells compared with COX-2-deficient tumors. CAY10678, an mPGES-1 inhibitor, was equivalent to celecoxib, a selective COX-2 inhibitor, in reinforcing anti-PD-1 treatment.
Our study indicates that mPGES-1 inhibitors represent a promising adjuvant for immunotherapies in melanoma by reducing collagen deposition and T-cell exhaustion. SIGNIFICANCE: Collagen is a predominant component of the extracellular matrix that may influence the tumor immune microenvironment for cancer progression.
We present here that mPGES-1 has specific roles in regulating tumor immunity, associated with several collagen-related genes and propose that pharmacologic inhibition of mPGES-1 may hold therapeutic promise for improving immune checkpoint-based therapies.
论文信息
- 作者
- Fukuda Y、Kim SH、Bustos MA、Cho SN、Roszik J、Burks JK、Kim H、Hoon DSB
- 单位
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Cancer research communications2023 Jul
- 原文标识
- PubMed 37529399 · DOI 10.1158/2767-9764.CRC-23-0210
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