結合TLR9與STING促進劑協同激活免疫反應並增強頭頸癌的抗腫瘤作用

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伊曼娜(Zaida Nur Imana) 查詢紙本館藏

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結合TLR9與STING促進劑協同激活免疫反應並增強頭頸癌的抗腫瘤作用
(Combination of TLR9 and STING Agonists Cooperatively Activates Immune Responses and Enhances Antitumor Effect on Head and Neck Cancer)

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至系統瀏覽論文 (2029-1-29以後開放)

摘要(中)

頭頸鱗狀細胞癌(HNSCC)主要包括口腔、咽、喉、鼻腔和唾液腺黏膜上皮的腫瘤等。該癌症的發生率在全球常見癌症中排名第六，凸顯其需要進一步開發新療法以增加患者康復和存活率的需求。模式識別受體(PRRs)的活化會引發先天免疫反應，隨後引發適應性免疫反應。由於其有效的免疫刺激活性有助於消滅癌細胞，因此不同的 PRR 刺激劑正在被研究以用於癌症免疫療法。為了研究體內的免疫機制和抗腫瘤功能，我們利用原位同基因頭頸癌小鼠模型。我們探討TLR9 刺激劑和 STING 刺激劑單獨或合併使用的免疫反應和抗腫瘤活性。在脾臟細胞、骨髓分化的巨噬細胞 (BMDM) 和樹突細胞 (BMDC) 中，CpG-2722 的刺激會增加 Th1 和 Th17 細胞因子的表現量，但不影響Th2 相關細胞因子的表現。與 CpG-2722 相比，STING 刺激劑顯示出誘導 Th1 和 Th17 表現量較低，但 Th2 細胞因子表現量較高的特性。然而，合併CpG-2722 與不同 STING 刺激劑可以增強 Th1 和 Th17，同時減少Th2 細胞激素的表現。CpG-2722 和 2’3’-c-di-AMP 能有效誘導細胞免疫反應，包括增加 IFN-γ、TNF-α、IL-1β、IL-6 和 IL-23A 細胞因子表現與樹突細胞成熟標記CD86、CD80、CD40和CCR7。在這些體外的實驗中，結合兩者皆能顯示出協同作用。此外，給予CpG-2722 和 2’3’-c-di-AMP 均能抑制頭頸癌腫瘤生長。與單獨處理相比，合併兩種刺激劑可以更有效的抑制腫瘤生長。在腫瘤微環境中，CpG-2722和2’3’-c-di-AMP合併治療協同促進IFN-γ、IL-12、IL-1β和type I IFN細胞因子的產生以及白血球、CD4和CD8 T細胞的累積、cDC和pDC的成熟以及增加M1腫瘤相關的巨噬細胞。綜合上述結果，我們認為在頭頸癌中，透過TLR9 和 STING 刺激劑的協同作用，可作為一種潛在的癌症免疫治療劑。

摘要(英)

Head and neck squamous cell carcinoma (HNSCC) constitute a group of tumors originating from mucosal epithelium in the oral cavity, pharynx, larynx, nasal cavity, and salivary glands. Globally, it ranks as the sixth most common cancer, highlighting the pressing need for the development of new therapies to enhance recovery and survival rates in patients. Activation of pattern recognition receptors (PRRs) initiates innate immune responses, subsequently triggering adaptive immune responses. Given their potent immune stimulatory properties that aid in the eradication of cancer cells, various PRR agonists are being investigated for cancer immune therapies. To investigate the immune mechanism and antitumor function in vivo, we utilized an orthotopic syngeneic head and neck cancer mouse model. We investigated the immune response and antitumor activities of TLR9 agonist and STING agonists, both individually and in combination. In splenocytes, bone marrow-derived macrophages (BMDMs) and bone marrow-derived dendritic cells (BMDCs), CpG-2722 showed increased expression of Th1 and Th17 cytokines but not Th2 cytokines. STING agonists exhibited lower expression of Th1 and Th17 but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of CpG-2722 with each STING agonist significantly enhanced Th1 and Th17 cytokine expressions while reducing Th2 cytokine expressions. CpG-2722 and 2’3’-c-di-AMP effectively induced cellular immune responses, including upregulation of IFN-γ, TNF-α, IL-1β, IL-6, and IL-23A cytokines expression, as well as maturation markers CD86, CD80, CD40, and CCR7 in DCs. Their combination demonstrated cooperative activity in vitro. Both CpG-2722 and 2’3’-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than using these agonists alone. In the tumor microenvironment, the combined treatment of CpG-2722 and 2’3’-c-di-AMP cooperatively promoted the production of IFN-γ, IL-12, IL-1β, and type I IFN cytokines. Additionally, it led to the accumulation of leukocytes, CD4, and CD8 T cells, maturation of cDCs and pDCs, and reprogramming of tumor-associated macrophages into M1 macrophages. Thus, this finding indicates the potent cancer immunotherapy agent through the cooperative activation of TLR9 and STING agonists in head and neck cancer.

關鍵字(中)

★ 頭頸癌
★ TLR9 激動劑
★ STING 激動劑
★ 免疫反應
★ 腫瘤微環境

關鍵字(英)

★ Head and neck cancer
★ TLR9 agonist
★ STING agonist
★ immune response
★ tumor microenvironment

論文目次

中文摘要 i
ABSTRACT ii
ACKNOWLEDGMENT iii
TABLE OF CONTENTS iv
LIST OF FIGURES vi
ABBREVIATION viii
CHAPTER I INTRODUCTION 1
1.1 Head and Neck Cancer 1
1.2 Tumor microenvironment 2
1.3 Strategies for cancer immunotherapy 6
1.4 Pathogen Recognition Receptors (PRRs) 9
1.5 Toll-like Receptors 9 (TLR9) 11
1.6 Stimulator of Interferon Genes (STING) 13
1.7 Specific Aims 14
CHAPTER II MATERIALS AND METHODS 16
2.1 Animal care 16
2.2 Chemicals, reagents, and antibodies 16
2.3 Cell culture 16
2.4 Mouse splenocytes preparation 16
2.5 Mouse bone marrow-derived dendritic cells (BMDCs) and bone marrow-derived macrophages (BMDMs) preparation 17
2.6 Splenocyte conditioned medium (SCM) preparation 17
2.7 RNA Isolation 18
2.8 Reverse transcription-quantitative PCR (RT-qPCR) analysis 19
2.9 Syngeneic orthotopic animal model of head and neck cancer 19
2.10 Immunohistochemistry 20
2.11 Statistical analysis 20
CHAPTER III RESULTS 21
3.1 Induction of cytokine expression by CpG-2722 and STING agonists alone 21
3.2 Induction of cytokine expression by CpG-2722 and STING agonists in combination 21
3.3 Induction of cytokine expression by CpG-2722 and 2‘3’-c-di-AMP alone or in combination 22
3.4 Dendritic cell maturation induced by CpG-2722 and 2’3’-c-di-AMP alone and their combination 23
3.5 Macrophage polarization was not promoted by CpG-2722 and 2’3’-c-di-AMP alone or in combination 23
3.6 Antitumor activity of CpG-2722 and 2’3’-c-di-AMP alone 24
3.7 Cooperative antitumor activities of CpG-2722 and 2’3’-c-di-AMP on head and neck cancer 24
3.8 Combination of CpG-2722 and 2’3’-c-di-AMP promotes Th1 cytokines and suppress Th2 cytokines in tumor microenvironment 25
3.9 Combination of CpG-2722 and 2’3’-c-di-AMP promotes immune cell accumulation in the tumor microenvironment 25
3.10 M1 macrophage polarization induced by splenocyte conditioned medium from Cp-2722 and 2’3’-c-di-AMP combination. 26
CHAPTER IV DISCUSSION 28
CHAPTER V CONCLUSION 35
REFERENCES 36
APPENDIX 69

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指導教授

莊宗顯王健家(Tsung-Hsien Chuang Chien-Chia Wang)

審核日期

2024-1-12

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