外泌体环状RNA在肿瘤免疫和癌症免疫治疗中的作用

doi:10.3877/cma.j.issn.1674-0785.2023.10.013

在癌症的发生发展中，肿瘤免疫起着至关重要的作用，免疫治疗已成为癌症治疗的里程碑。外泌体环状RNA具有成为无创性生物标志物的潜力，并且多项研究表明其参与肿瘤免疫和癌症免疫治疗耐药性。在这篇综述中，我们总结了外泌体环状RNA在调节肿瘤免疫、预测免疫治疗疗效方面的作用。外泌体环状RNA在癌症临床治疗中具有巨大前景。

关键词: 外泌体, 环状RNA, 肿瘤免疫, 免疫治疗, 生物标志物

Tumor immunity plays a significant role in the occurrence and development of cancer. Immunotherapy has become a milestone in cancer treatment. Exosomal circRNA have the potential to be noninvasive biomarkers. Several studies showed that exosomal circRNA involved in tumor immunity and cancer immunotherapy resistance. In this review, we summarized the role of exosomal circRNA in regulating tumor immunity and predicting immunotherapy efficacy. Exosomal circRNA has great prospects in the clinical treatment of cancer.

Key words: Exosome, Circular RNA (circRNA), Tumour immunity, Immunotherapy, Biomarker

表1 外泌体环状RNA在肿瘤免疫中的作用

癌症种类	分泌体环状RNA	表达	来源	受体细胞	通路	免疫功能	参考文献
肺癌	circZNF451 (hsa-circ-0002638)	↑	Cancer cell	Macrophages	FXR1/ ELF4/IRF4	Macrophages polarization、Anti-PD1 therapy resistance	^[18]
	circRNA-002178	↑	Cancer cell	T cell	miR-34/PDL1/PD1	PDL1/PD1 expression	^[19]
	circHIPK3	↑	Cancer cell	Macrophages	PTK2	M2 macrophage polarization	^[20]
	hsa_circ_0000190	↑	Cancer cell	T cell	Soluble PD-L1	Immune evasion	^[21]
	circUSP7 (hsa_circ_0005152)	↑	Cancer cell	T cell	miR-934/SHP2	Anti-PD1 therapy resistance	^[22]
	circFARSA	↑	Cancer cell	Macrophages	PTEN/PI3K/AKT	M2 macrophage polarization	^[16]
	circSHKBP1 (hsa_circ_0000936)	↑	Cancer cell	Macrophages	PKM2	M2 polarization and macrophage recruitment	^[23]
胃癌	hsa_circ_0017252	↓	Cancer cell	Macrophages	miR-17-5p	Macrophage M2 polarization	^[25]
食管癌	Circ0048117	↑	Cancer cell	Macrophages	miR-140/ TLR4	M2 Macrophage Polarization	^[26]
胆管癌	Circ_0020256 (hsa_Circ_0020256)	↑	Tumor-associated macrophages	NA	miR-432-5p/E2F3	NA	^[40]
	circ-PTPN22（hsa_circ_0110529）	↑	Cancer cell	T cell、Neutrophil、Macrophages	NA	T cell exhaustion and neutrophil extracellular traps	^[27]
	circ-ADAMTS6（hsa_circ_0072688）	↑	Cancer cell	T cell、Neutrophil、Macrophages	NA	T cell exhaustion and neutrophil extracellular traps	^[27]
肝细胞癌	circGSE1（hsa_circ_0000722）	↑	Cancer cell	Regulatory T cell	miR-324-5p/TGFBR1/Smad3	Expansion of regulatory T cells	^[28]
	circTMEM181（hsa_circ_0001663）	↑	Cancer cell	Macrophages	miR-488-3p/CD39	Anti-PD1 therapy resistance	^[29]
	hsa_circ_0074854	↑	Cancer cell	Macrophages	Human antigen R (HuR)	Macrophage M2 Polarization	^[30]
	circUHRF1（hsa_circ_0048677）	↑	Cancer cell	NK cell	miR-449c-5p/TIM-3	Impairment of IFN-γ and TNF-α secretion in NK cells、Anti-PD1 therapy resistance	^[31]
	hsa_circ_0004658	↑	RBPJ-overexpressed macrophages	NA	miR-499b-5p/JAM3	NA	^[43]
结直肠癌	hsa_circ_0050334	↑	Cancer cell	macrophages	hsa_miR_182_5p/RGS2	Survival	^[32]
	CircPACRGL	↑	Cancer cell	Neutrophil	miR-142-3p/miR-506-3p/TGF-β1	Differentiation of N1 to N2 neutrophils	^[33]
	CircEIF3K	↑	Cancer-associated fibroblast	NA	miR-214/PD-L1	NA	^[46]
胰腺导管腺癌	Circ_0006790	↑	Bone marrow mesenchymal stem cell	T cells	CBX7/S100A11	Killing effects of T cells	^[48]
肾细胞癌	circSAFB2	↑	Cancer cell	Macrophages	miR-620/JAK1/STAT3	M2 Macrophage Polarization	^[34]
口腔鳞状细胞癌	hsa_circ_0069313	↑	Cancer cell	Regulatory T cell	miR-325-3p/Foxp3	CD8+ T cell infiltration	^[35]
胶质瘤	circNEIL3（hsa_circ_0001460）	↑	Cancer cell	Tumour associated macrophages	IGF2BP3/YAP1	Macrophage infiltration	^[33]
胶质瘤	circBTG2	↑	RBPJ-overexpressed macrophages	NA	miR-25-3p/PTEN	NA	^[44]
乳腺癌	circPSMA1	↑	Cancer cell	NA	miR-637/Akt1/β-catenin（cyclin D1）	Immunosuppression	^[36]
乳腺癌	circ_0001142（hsa_circ_0001142）	↑	Cancer cell	Macrophages	miR-361-3p /PIK3CB	M2 Macrophage Polarization	^[37]
卵巢癌	Circ0001068（hsa_circ_0001068）	↑	Cancer cell	T cell	miR-28-5P/PD1	T cell apoptosis, disintegration	^[38]
子宫内膜癌	hsa_circ_0001610	↑	Tumor-associated macrophage	NA	miR-139-5p	NA	^[41]
前列腺癌	circMID1（hsa_circ_0007718）	↑	Myeloid-derived suppressor cells	NA	miR-506-3p/MID1	NA	^[51]

表1 外泌体环状RNA在肿瘤免疫中的作用

癌症种类	分泌体环状RNA	表达	来源	受体细胞	通路	免疫功能	参考文献
肺癌	circZNF451 (hsa-circ-0002638)	↑	Cancer cell	Macrophages	FXR1/ ELF4/IRF4	Macrophages polarization、Anti-PD1 therapy resistance	^[18]
	circRNA-002178	↑	Cancer cell	T cell	miR-34/PDL1/PD1	PDL1/PD1 expression	^[19]
	circHIPK3	↑	Cancer cell	Macrophages	PTK2	M2 macrophage polarization	^[20]
	hsa_circ_0000190	↑	Cancer cell	T cell	Soluble PD-L1	Immune evasion	^[21]
	circUSP7 (hsa_circ_0005152)	↑	Cancer cell	T cell	miR-934/SHP2	Anti-PD1 therapy resistance	^[22]
	circFARSA	↑	Cancer cell	Macrophages	PTEN/PI3K/AKT	M2 macrophage polarization	^[16]
	circSHKBP1 (hsa_circ_0000936)	↑	Cancer cell	Macrophages	PKM2	M2 polarization and macrophage recruitment	^[23]
胃癌	hsa_circ_0017252	↓	Cancer cell	Macrophages	miR-17-5p	Macrophage M2 polarization	^[25]
食管癌	Circ0048117	↑	Cancer cell	Macrophages	miR-140/ TLR4	M2 Macrophage Polarization	^[26]
胆管癌	Circ_0020256 (hsa_Circ_0020256)	↑	Tumor-associated macrophages	NA	miR-432-5p/E2F3	NA	^[40]
	circ-PTPN22（hsa_circ_0110529）	↑	Cancer cell	T cell、Neutrophil、Macrophages	NA	T cell exhaustion and neutrophil extracellular traps	^[27]
	circ-ADAMTS6（hsa_circ_0072688）	↑	Cancer cell	T cell、Neutrophil、Macrophages	NA	T cell exhaustion and neutrophil extracellular traps	^[27]
肝细胞癌	circGSE1（hsa_circ_0000722）	↑	Cancer cell	Regulatory T cell	miR-324-5p/TGFBR1/Smad3	Expansion of regulatory T cells	^[28]
	circTMEM181（hsa_circ_0001663）	↑	Cancer cell	Macrophages	miR-488-3p/CD39	Anti-PD1 therapy resistance	^[29]
	hsa_circ_0074854	↑	Cancer cell	Macrophages	Human antigen R (HuR)	Macrophage M2 Polarization	^[30]
	circUHRF1（hsa_circ_0048677）	↑	Cancer cell	NK cell	miR-449c-5p/TIM-3	Impairment of IFN-γ and TNF-α secretion in NK cells、Anti-PD1 therapy resistance	^[31]
	hsa_circ_0004658	↑	RBPJ-overexpressed macrophages	NA	miR-499b-5p/JAM3	NA	^[43]
结直肠癌	hsa_circ_0050334	↑	Cancer cell	macrophages	hsa_miR_182_5p/RGS2	Survival	^[32]
	CircPACRGL	↑	Cancer cell	Neutrophil	miR-142-3p/miR-506-3p/TGF-β1	Differentiation of N1 to N2 neutrophils	^[33]
	CircEIF3K	↑	Cancer-associated fibroblast	NA	miR-214/PD-L1	NA	^[46]
胰腺导管腺癌	Circ_0006790	↑	Bone marrow mesenchymal stem cell	T cells	CBX7/S100A11	Killing effects of T cells	^[48]
肾细胞癌	circSAFB2	↑	Cancer cell	Macrophages	miR-620/JAK1/STAT3	M2 Macrophage Polarization	^[34]
口腔鳞状细胞癌	hsa_circ_0069313	↑	Cancer cell	Regulatory T cell	miR-325-3p/Foxp3	CD8+ T cell infiltration	^[35]
胶质瘤	circNEIL3（hsa_circ_0001460）	↑	Cancer cell	Tumour associated macrophages	IGF2BP3/YAP1	Macrophage infiltration	^[33]
胶质瘤	circBTG2	↑	RBPJ-overexpressed macrophages	NA	miR-25-3p/PTEN	NA	^[44]
乳腺癌	circPSMA1	↑	Cancer cell	NA	miR-637/Akt1/β-catenin（cyclin D1）	Immunosuppression	^[36]
乳腺癌	circ_0001142（hsa_circ_0001142）	↑	Cancer cell	Macrophages	miR-361-3p /PIK3CB	M2 Macrophage Polarization	^[37]
卵巢癌	Circ0001068（hsa_circ_0001068）	↑	Cancer cell	T cell	miR-28-5P/PD1	T cell apoptosis, disintegration	^[38]
子宫内膜癌	hsa_circ_0001610	↑	Tumor-associated macrophage	NA	miR-139-5p	NA	^[41]
前列腺癌	circMID1（hsa_circ_0007718）	↑	Myeloid-derived suppressor cells	NA	miR-506-3p/MID1	NA	^[51]

图1 外泌体环状RNA的肿瘤免疫机制研究在不同癌种中的分布

图2 外泌体环状RNA在癌症抗PD1治疗耐药中的作用

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Roles of exosomal circRNA in tumour immunity and cancer immunotherapy

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Roles of exosomal circRNA in tumour immunity and cancer immunotherapy