药学学报

Drug name	Chemical structure	IC₅₀/nmol·L^-1	Mechanism	Indication	Clinical status
PHPS1		1 380	It alleviates the pulmonary inflammatory response by modulating immune cells	Pulmonary inflammation	Preclinical
SHP099		70	It promotes cytokine/granule production by cytotoxic T cells to exert tumor immunomodulatory effects	Colon cancer	Preclinical
RMC-4550		0.58	It directly impacts the survival and function of suppressive monocytic immune cells	Colon cancer	Preclinical
RMC-4630	/	/	It increases T cell infiltration, selectively depletes M2 type macrophages	Non-small cell lung cancer	Phase Ⅱ
TNO155		11	It can inhibit immune-suppressive macrophages	Ovarian cancer, breast cancer, colorectal cancer, colon cancer	Phase Ⅰ/Ⅱ
JAB-3068		/	It can block the PD-1 pathway of T cells, enhance the ability of CD8⁺ T cells, and inhibit TAM function	Advanced or metastatic solid tumors	Phase Ⅱ
JAB-3312	/	/	Phase Ⅰ/Ⅱ
BBP398		16	It can inhibit tumor growth by blocking RAS-ERK signaling and can be combined with PD-1 antibodies	Advanced solid tumors with a KRAS mutation	Phase Ⅰ
HBI-2376		/	It can inhibit tumor growth by inducing the activity of immune infiltrating cells	Solid tumors with KRAS or EGFR mutations	Phase Ⅰ
ICP-189	/	/	It can restore Th1 immune function and activate T cells, thereby triggering the immune response	Solid tumors such as lung cancer, head and neck cancer and gastrointestinal cancer	Phase Ⅰ
Trichomide A		/	It can effectively inhibit the proliferation of activated T cells and the production of pro-inflammatory cytokines	Immune-related skin diseases	Preclinical
Fusaruside		/	It can inhibit STAT1/T-bet signaling and rebuild the balance of STAT1 and STAT3 signaling	Colitis, hepatitis	Preclinical

Drug name	Chemical structure	IC₅₀/nmol·L^-1	Mechanism	Indication	Clinical status
PHPS1		1 380	It alleviates the pulmonary inflammatory response by modulating immune cells	Pulmonary inflammation	Preclinical
SHP099		70	It promotes cytokine/granule production by cytotoxic T cells to exert tumor immunomodulatory effects	Colon cancer	Preclinical
RMC-4550		0.58	It directly impacts the survival and function of suppressive monocytic immune cells	Colon cancer	Preclinical
RMC-4630	/	/	It increases T cell infiltration, selectively depletes M2 type macrophages	Non-small cell lung cancer	Phase Ⅱ
TNO155		11	It can inhibit immune-suppressive macrophages	Ovarian cancer, breast cancer, colorectal cancer, colon cancer	Phase Ⅰ/Ⅱ
JAB-3068		/	It can block the PD-1 pathway of T cells, enhance the ability of CD8⁺ T cells, and inhibit TAM function	Advanced or metastatic solid tumors	Phase Ⅱ
JAB-3312	/	/	Phase Ⅰ/Ⅱ
BBP398		16	It can inhibit tumor growth by blocking RAS-ERK signaling and can be combined with PD-1 antibodies	Advanced solid tumors with a KRAS mutation	Phase Ⅰ
HBI-2376		/	It can inhibit tumor growth by inducing the activity of immune infiltrating cells	Solid tumors with KRAS or EGFR mutations	Phase Ⅰ
ICP-189	/	/	It can restore Th1 immune function and activate T cells, thereby triggering the immune response	Solid tumors such as lung cancer, head and neck cancer and gastrointestinal cancer	Phase Ⅰ
Trichomide A		/	It can effectively inhibit the proliferation of activated T cells and the production of pro-inflammatory cytokines	Immune-related skin diseases	Preclinical
Fusaruside		/	It can inhibit STAT1/T-bet signaling and rebuild the balance of STAT1 and STAT3 signaling	Colitis, hepatitis	Preclinical

Drug name	Chemical structure	Corporation	PD-1/PD-L1 antibody	Indication	Clinical status
SHP099		Novartis	RMP1-14	Colon cancer	Preclinical
TNO155		Novartis	Spartalizumab	Non-small cell lung carcinoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastrointestinal stromal tumors, colorectal cancer	Phase Ⅰ
RMC-4630	/	Revolution Medicine	Pembrolizumab	Metastatic lung cancer	Phase Ⅰ/Ⅱ
ERAS-601	/	Erasca	Pembrolizumab	HPV negative advanced or metastatic head and neck squamous cell carcinoma or non-small cell lung cancer	Phase Ⅰ
JAB-3068		Jacobio	Toripalimab	Esophageal squamous cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma	Phase Ⅰ/Ⅱ
JAB-3312	/	Jacobio	Pembrolizumab	Non-small cell lung cancer	Phase Ⅰ/Ⅱ
BBP398		Navire Pharma	Nivolumab	Advanced non-small cell lung cancer with a KRAS mutation	Phase Ⅰ
GDC-1971		Genentech	Atezolizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma	Phase Ⅰ
BR790	/	Gopherwood Biotech	Tislelizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma	Phase Ⅰ/Ⅱ

Drug name	Chemical structure	Corporation	PD-1/PD-L1 antibody	Indication	Clinical status
SHP099		Novartis	RMP1-14	Colon cancer	Preclinical
TNO155		Novartis	Spartalizumab	Non-small cell lung carcinoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastrointestinal stromal tumors, colorectal cancer	Phase Ⅰ
RMC-4630	/	Revolution Medicine	Pembrolizumab	Metastatic lung cancer	Phase Ⅰ/Ⅱ
ERAS-601	/	Erasca	Pembrolizumab	HPV negative advanced or metastatic head and neck squamous cell carcinoma or non-small cell lung cancer	Phase Ⅰ
JAB-3068		Jacobio	Toripalimab	Esophageal squamous cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma	Phase Ⅰ/Ⅱ
JAB-3312	/	Jacobio	Pembrolizumab	Non-small cell lung cancer	Phase Ⅰ/Ⅱ
BBP398		Navire Pharma	Nivolumab	Advanced non-small cell lung cancer with a KRAS mutation	Phase Ⅰ
GDC-1971		Genentech	Atezolizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma	Phase Ⅰ
BR790	/	Gopherwood Biotech	Tislelizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma	Phase Ⅰ/Ⅱ

Drug name	Corporation	Kinase targeted agent	Indication	Clinical status
SHP099	Novartis	ARS1620	KRAS^G12C-mutant PDAC and NSCLC	Preclinical
RMC-4550	Revolution Medicine	Abemaciclib	Breast cancer	Preclinical

Drug name	Corporation	Kinase targeted agent	Indication	Clinical status
SHP099	Novartis	ARS1620	KRAS^G12C-mutant PDAC and NSCLC	Preclinical
RMC-4550	Revolution Medicine	Abemaciclib	Breast cancer	Preclinical

SHP2调节剂在肿瘤免疫治疗中的研究进展

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杨欣语 ¹^,² , 尚佳文 ¹ , 于海云 ¹ , 宋宜辉 ¹^,²^,^* , 余斌 ¹^,²^,^*

药学学报 | 综述 2023,58(8): 2226-2238

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药学学报 |综述 2023 , 58 (8) : 2226 -2238

SHP2调节剂在肿瘤免疫治疗中的研究进展

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杨欣语¹^,², 尚佳文¹, 于海云¹, 宋宜辉¹^,²^,^*, 余斌¹^,²^,^*

作者信息

1.郑州大学药学院药物研究院, 河南郑州 450001

2.药物关键制备技术教育部重点实验室, 河南郑州 450001

通讯作者:

*宋宜辉, Tel: 86-371-67781908, E-mail: songyihui@zzu.edu.cn;

余斌, E-mail: yubin@zzu.edu.cn

Advances of SHP2 modulators in the cancer immunotherapy

Xin-yu YANG¹^,², Jia-wen SHANG¹, Hai-yun YU¹, Yi-hui SONG¹^,²^,^*, Bin YU¹^,²^,^*

Affiliations

1. School and Institute of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

2. Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou 450001, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0628

文章导航

摘要

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Src同源酪氨酸磷酸酶2 (Src homology phosphotyrosyl phosphatase 2, SHP2) 是由PTPN11编码的蛋白酪氨酸磷酸酶, 可催化蛋白酪氨酸位点的去磷酸化。作为汇聚节点, SHP2介导鼠肉瘤(rat sarcoma, RAS)-快速加速纤维肉瘤(rapidly accelerated fibrosarcoma, RAF)-丝裂原活化细胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase, MEK)-细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK)、磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinase, PI3K)-丝氨酸/苏氨酸蛋白激酶(serine/threonine kinase, AKT)、Janus激酶(janus kinase, JAK)-信号转导和转录激活因子(signal transducer and activator of transcription, STAT) 和程序性死亡受体1 (programmed death-1, PD-1)/程序性死亡受体-配体1 (programmed cell death-ligand 1, PD-L1) 等多个信号通路, 不仅可调控肿瘤细胞的生长增殖, 还可通过影响肿瘤微环境介导肿瘤细胞的免疫逃逸, 在肿瘤免疫调控中发挥双重生物学功能, 是一种很有前景的肿瘤免疫治疗靶点。截止目前, 已有多种SHP2变构抑制剂开展了单一或联合用药策略的肿瘤免疫治疗临床研究, 此外SHP2激活剂也在肿瘤免疫调控领域呈现出治疗潜力。本文综述了SHP2在肿瘤细胞和免疫细胞中的双重肿瘤免疫调控功能, 概述了目前SHP2调节剂在肿瘤免疫治疗领域的最新研究进展, 并对该领域的研究挑战和应用前景进行了讨论和展望, 旨在开拓SHP2调节剂在肿瘤免疫治疗领域的新视野。

关键词

蛋白质磷酸化 / 蛋白酪氨酸磷酸酶 / SHP2 / 肿瘤免疫调控 / SHP2调节剂

Abstract

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Src homology phosphotyrosyl phosphatase 2 (SHP2) is a protein tyrosine phosphatase encoded by PTPN11, which catalyzes the dephosphorylation of protein tyrosine. As a convergence node, SHP2 mediates multiple signaling pathways such as rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated extracellular signal-regulated kinase (MEK)-extracellular regulated protein kinases (ERK), phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (AKT), janus kinase (JAK)-signal transducer and activator of transcription (STAT) and programmed death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1). It can not only regulate the growth and proliferation of tumor cells, but also mediate the immune escape of tumor cells by influencing the tumor microenvironment. Given its dual biological functions in tumor immune regulation, SHP2 is a promising target for cancer immunotherapy. To date, several SHP2 allosteric inhibitors have been advanced into clinical trials for tumor immunotherapy with single or combination therapeutic strategies. Additionally, SHP2 activators also showed therapeutic potential in the field of tumor immune modulation. In this paper, we reviewed the dual function of SHP2 in both tumor and immune cells. Besides, the challenges and prospects of SHP2 modulators in cancer immunotherapy were also briefly discussed, aiming to explore new horizon of SHP2 modulators for tumor immunotherapy.

Key words

protein phosphorylation / protein tyrosine phosphatase / SHP2 / tumor immune modulation / SHP2 modulator

引用本文

杨欣语, 尚佳文, 于海云, 宋宜辉, 余斌. SHP2调节剂在肿瘤免疫治疗中的研究进展. 药学学报, 2023 , 58 (8) : 2226 -2238 . DOI: 10.16438/j.0513-4870.2023-0628

Xin-yu YANG, Jia-wen SHANG, Hai-yun YU, Yi-hui SONG, Bin YU. Advances of SHP2 modulators in the cancer immunotherapy[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2226 -2238 . DOI: 10.16438/j.0513-4870.2023-0628

正文

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蛋白质磷酸化是一种由蛋白激酶和蛋白磷酸酶协同调控的可逆、动态的翻译后修饰过程, 在细胞增殖、侵袭、分化、代谢和耐药等生物学过程中发挥着重要的作用^[1]。SHP2 (Src homology phosphotyrosyl phosphatase 2, SHP2) 是一种由原癌基因PTPN11编码, 在细胞质中广泛存在的非受体型蛋白酪氨酸磷酸酶(protein tyrosine phosphatas, PTPs)^{[2, 3]}。SHP2主要由四个部分组成, 包括两个Src同源2 (Src homology 2, SH2) 结构域(N-SH2和C-SH2)、一个高度保守的PTP催化结构域和含有磷酸化位点的C端尾部^{[4, 5]}。

SHP2是鼠肉瘤(rat sarcoma, RAS)-快速加速纤维肉瘤(rapidly accelerated fibrosarcoma, RAF)-丝裂原活化细胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase, MEK)-细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK)、磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinase, PI3K)-丝氨酸/苏氨酸蛋白激酶(serine/threonine kinase, AKT)、Janus激酶(janus kinase, JAK)-信号转导和转录激活因子(signal transducer and activator of transcription, STAT) 和程序性死亡受体1 (programmed death-1, PD-1)/程序性死亡受体-配体1 (programmed cell death-ligand 1, PD-L1) 等多个信号通路中的关键调控因子, 其失调一方面可直接促进肿瘤细胞的生长和增殖, 另一方面可通过改变肿瘤微环境而调控抗肿瘤免疫^[6]。目前SHP2与免疫相关的作用机制有: ①在T细胞中, SHP2可通过与免疫抑制受体PD-1、细胞毒性T淋巴细胞相关抗原4 (cytotoxic T lymphocyte-associated antigen-4, CTLA-4)、B和T淋巴细胞衰减因子(B and T lymphocyte attenuator, BTLA)、T细胞免疫球蛋白和免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitory motif, ITIM) 结构域蛋白(T cell immune receptor with immunoglobulin and ITIM domain, TIGIT)、T细胞受体(T cell receptor, TCR) 和分化决定簇28 (cluster of differentiation 28, CD28) 相互作用而抑制T细胞的活化, 降低抗肿瘤免疫能力, 进而发挥免疫抑制作用^[7-11]; ②在巨噬细胞中, SHP2通过与集落刺激因子1 (colony stimulating factor 1, CSF-1)/集落刺激因子1受体(colony stimulating factor 1 receptor, CSF-1R)、分化决定簇47 (cluster of differentiation 47, CD47)/信号调节蛋白α (signal regulatory protein α, SIRPα)、分化决定簇24 (cluster of differentiation 24, CD24)/唾液酸结合Ig样凝集素10 (sialic acid binding ig like lectin 10, siglec-10)、白细胞介素10 (interleukin-10, IL-10)/白细胞介素10受体(interleukin-10 receptor, IL-10R)、肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)/肿瘤坏死因子受体1 (tumor necrosis factor receptor 1, TNFR1) 相互作用促进巨噬细胞的增殖和M2型巨噬细胞的极化, 削弱巨噬细胞的吞噬作用, 介导肿瘤细胞免疫逃逸^[12-16]; ③除T细胞和巨噬细胞外, SHP2对B细胞、自然杀伤细胞(natural killer cell, NK) 和树突状细胞(dendritic cell, DC) 等免疫细胞的作用仍有待进一步研究^[16]。

SHP2失调可导致其介导信号通路的异常活化, 在多数恶性疾病如幼年型粒单核细胞白血病(juvenile myelomonocytic leukemias, JMML)、努南氏综合征(Noonan syndrome, NS)、LEOPARD综合征(LEOPARD syndrome, LS)、骨髓增生异常综合征(myelodysplasic syndromes, MDS)、前体B细胞急性淋巴细胞白血病(B-precursor acute lymphoblastic leukemias, B-ALL) 和急性髓细胞白血病(acute myeloid leukemias, AML) 等血液瘤和发育障碍疾病, 以及乳腺癌、宫颈癌、非小细胞肺癌(non-small cell lung cancer, NSCLC)、原发性肝癌和食管鳞状细胞癌等实体瘤的发生发展中扮演着重要角色, 是肿瘤靶向治疗的一个重要药物作用靶标^{[4, 17]}。目前报道的SHP2靶向药物主要包括抑制剂、激活剂、靶向蛋白-蛋白相互作用(protein-protein interaction, PPI) 抑制剂和基于蛋白降解靶向嵌合体(proteolysis targeting chimera, PROTAC) 的降解剂四大类, 可通过抑制肿瘤生长或调节肿瘤微环境而发挥抗肿瘤作用^[18]。值得一提的是, 包括TNO155、RMC-4550、RMC-4630、ERAS-601、JAB-3068、JAB-3312、BBP398、HBI-2376、ICP-189、GDC-1971和BR790在内的多种SHP2变构抑制剂已作为单一或联合抗肿瘤免疫治疗方案进入临床研究^[19-26]。此外, 激活剂如trichomide A和fusaruside也在肿瘤免疫治疗中表现出显著的应用潜力^{[27, 28]}。

针对SHP2调节剂在肿瘤免疫治疗领域的最新研究进展, 本文系统综述了SHP2在肿瘤免疫调节中的双重生物学功能, 强调了其在不同免疫细胞中的调节机制, 并全面总结了靶向SHP2的抑制剂和激活剂在肿瘤免疫治疗中的研究进展。此外, 本文还对SHP2调节剂在肿瘤免疫治疗中的应用前景和挑战进行了展望, 旨在为SHP2调节剂在肿瘤免疫调控中的应用提供一个全景图。

1 SHP2在肿瘤免疫调控中的双重生物学功能

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1.1 SHP2在肿瘤细胞中的“双刃剑”作用

在细胞因子或生长因子等细胞外信号的刺激下, SHP2可以通过与生长因子受体结合蛋白2 (growth factor receptor-bound protein 2, Grb2)/鸟苷酸交换因子非七激酶子(son of sevenless, SOS)、Grb2相关结合蛋白1 (Grb2 associated binder-1, Gab1)、RasGTP酶激活蛋白(Ras GTPase-activating protein, RasGAP) 以及Sprouty (Spry) 蛋白等相互作用参与RAS-RAF-MEK-ERK、PI3K-AKT-雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR) 和JAK-STAT通路的调控, 介导细胞生长、增殖、分化和迁移等生物学效应^[29-31]。研究表明SHP2既可以作为致癌因子, 也可以作为抑癌因子参与调控肿瘤细胞的增殖、分化、侵袭和转移, 与肿瘤的发生发展和预后密切相关(图 1)^[4]。通常, PTPN11突变与血液系统恶性肿瘤和发育障碍疾病的高频率发生相关, 包括35%的幼年型粒细胞白血病, 50%的努南氏综合征, 80%的LEOPARD综合征, 10%的骨髓增生异常综合征, 7%的前体B细胞急性淋巴细胞白血病和5%的急性髓细胞白血病^[32-35]。此外, 通过与鼠类肉瘤病毒癌基因(kirsten rat sarcoma virus, KRAS) 和表皮生长因子受体(epidermal growth factor receptor, EGFR) 等其他上游信号因子突变的协同作用, SHP2过表达或突变也参与了乳腺癌、肺癌、肝癌、胃癌、喉癌、口腔癌等实体瘤的发生发展^[4]。在不同生物学背景下, SHP2基于底物特异性的“双刃剑”功能显著增加了其在不同疾病中的功能复杂性^[4]。

SHP2在多数肿瘤中发挥致癌作用^[36-38]。如在肺癌组织中, SHP2的表达明显高于周围正常肺组织。SHP2可能通过激活丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 信号转导而促进肺癌细胞的增殖、迁移和侵袭能力^[36]。在乳腺癌中, SHP2主要通过PI3K-AKT-糖原合成酶激酶-3β (glycogen synthase kinase-3β, GSK3β) 信号通路调节细胞周期蛋白D1的稳定性来促进乳腺癌细胞的增殖^[37]。在前列腺癌中, SHP2可正性调节P2Y嘌呤受体介导的ERK的活化, 促进肿瘤细胞的体外侵袭能力^[38]。在一些肿瘤中, SHP2也可发挥一定的抑癌作用, 抑制STAT3信号通路激活可能是SHP2发挥抑癌作用的重要分子机制^[39]。如SHP2在肺腺癌细胞A549中发挥抑癌作用, 抑制SHP2的活性不仅可促进肺腺癌细胞的增殖, 而且可导致A549细胞对顺铂的耐药性, 抑制细胞凋亡^[40]。此外, SHP2在肿瘤发生发展中的双重作用还体现在同种肿瘤发生发展的不同阶段, 其作用的差异取决于细胞的异质性及SHP2参与调控信号通路的不同。研究发现抑制SHP2在肝癌发生的早期阶段发挥抑制作用, 而在疾病后期发挥促进作用^[41]。在肝癌中, SHP2发挥促癌还是抑癌作用一直存在争议, 具体病理原因仍有待进一步探究。

1.2 SHP2在免疫细胞中的调控作用

SHP2不仅可调控肿瘤细胞的生长增殖, 而且可参与多种免疫细胞介导的肿瘤免疫调控信号通路, 共同介导肿瘤的发生发展^[29]。目前对SHP2在T淋巴细胞和巨噬细胞中的研究较全面, 但对其在B淋巴细胞、NK细胞、DC细胞等抗原呈递细胞(antigen presenting cell, APC) 中的研究却鲜有报道^[16]。

在T细胞中, PD-1可通过尾部的ITIM以及免疫受体酪氨酸开关基序(immunoreceptor tyrosine based switch motif, ITSM) 与SHP2的两个SH2结构域结合招募SHP2^{[42, 43]}。SHP2被募集后可促进zeta相关蛋白70 (70-kDa zeta-associated protein, ZAP70) 和CD28的去磷酸化, 抑制RAS-ERK、PI3K-AKT和蛋白激酶C-θ (protein kinase C-θ, PKC-θ) 信号转导, 进而削弱转录因子如激活蛋白1 (activator protein-1, AP-1)、活化T细胞核因子(nuclear factor of activated T cell, NFAT)、mTOR和核因子κB (nuclear factor kappa-B, NF-κB) 的活化^{[16, 44]}。此外, SHP2还可特异性地去磷酸化PD-1下游因子白细胞介素2诱导型T细胞激酶(interleukin 2-inducible T-cell kinase, ITK), 抑制T细胞的活化^[45]。除PD-1信号通路外, SHP2还可参与其他免疫检查点途径来调控T细胞的活化^[16]。如CTLA-4尾部酪氨酸-缬氨酸-赖氨酸-甲硫氨酸(Tyr-Val-Lys-Met, YVKM) 基序的磷酸化可以募集SHP2, 导致CD28的去磷酸化并抑制CD28信号转导, 从而负调控T细胞介导的免疫调控^[46]。BTLA和TIGIT也可通过ITIM基序募集SHP2进而抑制T细胞的活性, 但其具体机制仍需进一步研究(图 2)^[16]。通过分析头颈部鳞状细胞癌患者的肿瘤浸润淋巴细胞和外周血淋巴细胞发现, PD-1可通过募集激活SHP2而抑制PD-1-SHP2-STAT1-T盒子转录因子(T-box expressed in T cell, T-bet) 信号轴介导的辅助性T细胞1 (T help cell 1, Th1) 免疫反应, 并抑制Th1细胞因子干扰素-γ (interferon γ, IFN-γ)、TNF-α和IL-2的产生而抑制T细胞的活化, 调控肿瘤微环境^{[16, 47]}。

在巨噬细胞中, CSF-1的刺激可诱导SHP2与CSF-1R/Grb2/Gab2复合物的结合, 激活RAS-ERK信号通路, 促进肿瘤细胞的存活、增殖和迁移^[48]。CD47/SIRPα途径也是调控巨噬细胞的重要通路。SIRPα的胞外NH₂末端可与CD47结合, 导致ITIMs上的酪氨酸磷酸化, 进而募集SHP2, 抑制巨噬细胞介导的吞噬作用^{[49, 50]}。Siglec-10与CD24结合后其ITIM可以募集并激活SHP2, 阻断巨噬细胞吞噬所需的细胞骨架重排, 触发抑制性信号转导级联反应, 抑制巨噬细胞对肿瘤细胞的吞噬作用, 进而介导肿瘤免疫逃逸(图 3)^[49]。此外, SHP2对巨噬细胞的负调节作用已在多种癌症如胰腺导管腺癌和黑色素瘤等中被证实。在胰腺导管腺癌小鼠模型中, 抑制髓样生长因子受体CSF-1R的信号传导可在功能上重新编程巨噬细胞, 增强抗原呈递并产生有效的抗肿瘤T细胞反应^[51]。在黑色素瘤中, 髓系SHP2可通过抑制巨噬细胞/趋化因子CXC配体9 (C-X-C motif chemokine ligand 9, CXCL9)/T细胞/IFN-γ反馈回路而抑制T细胞介导的抗肿瘤免疫, 暗示靶向巨噬细胞SHP2可能有助于构建Th1型肿瘤免疫微环境^[52]。

在B细胞中, SHP2通过双重作用调控肿瘤免疫反应。一方面, SHP2可发挥正调节作用, SHP2活化与IL-6诱导的B细胞增殖密切相关^[53]。另一方面, SHP2可作为负调节因子。B细胞受体(B cell receptor, BCR) 与携带ITIM的抑制受体PD-1结合后, SHP2被募集到PD-1中, 诱导BCR的关键信号元件如免疫球蛋白关联β (immunoglobulin β, Igβ)、脾酪氨酸激酶(spleen tyrosine kinase, Syk) 和磷脂酶Cγ (phospholipase Cγ, PLCγ) 的去磷酸化^[54]。同样当B细胞受体与Fcγ受体IIb (Fcγ receptor IIb, FcγRIIb) 结合后, 将募集SHP2并使衔接蛋白Gab1去磷酸化, 干扰PI3K的活化, 进而抑制B细胞的活化与存活, 调控肿瘤免疫反应(图 4)^[55]。

在NK细胞中, NK细胞表面的一些抑制受体也可通过ITIM基序募集和激活SHP2, SHP2可通过去磷酸化杀伤细胞免疫球蛋白样受体(killer cell ig-like receptor, KIR)、Syk、Zap70等分子进而抑制NK细胞的活化(图 5)^[56]。SHP2敲除的NK细胞对肿瘤靶细胞具有更强的细胞溶解活性和IFN-γ产生能力^[57]。然而使用敲除SHP2的NK细胞系小鼠模型研究证明: NK细胞的发育和响应能力在很大程度上不受SHP2影响^[58]。因此SHP2在NK细胞中的具体调控机制仍存在较大争议。

除上述细胞外, SHP2也参与其他免疫细胞如DC细胞的肿瘤免疫调控。研究表明SHP2敲除可抑制骨髓源树突状细胞(bone marrow-derived dendritic cells, BMDC) 的迁移, 树突状细胞迁移到淋巴结对于适应性免疫反应的启动和发展至关重要。此外, 脂多糖刺激SHP2缺失的BMDC后, 将增加Rho型鸟嘌呤核苷酸交换因子(Rho-specific guanine nucleotide exchange factor, p115RhoGEF) 的磷酸化并增强三磷酸鸟苷(guanosine triohosphte, GTP) 的活性。Rho-GTP活性的增加促进了肌球蛋白轻链(myosin light chain, MLC)、丝切蛋白(cofilin, CFL) 和富含脯氨酸的酪氨酸激酶2 (proline-rich tyrosine kinase 2, Pyk2) 的磷酸化, 抑制DC细胞的迁移^[59]。但SHP2在其他免疫细胞如粒细胞、髓源性抑制细胞(myeloid-derived suppressor cells, MDSCs) 和肥大细胞中的报道较少, 仍有待进一步研究。

2 SHP2调节剂在肿瘤免疫调控中的研究进展

收起

靶向SHP2的药物研发策略包括抑制剂、激活剂、PPI抑制剂和PROTAC降解剂, 其中SHP2抑制剂是目前靶向SHP2的抗肿瘤药物研发领域的研究热点^[60]。本部分系统总结了SHP2调节剂的单药和联合治疗在肿瘤免疫调控领域的研究进展, 期望为SHP2调节剂在肿瘤免疫领域的应用奠定基础。

2.1 SHP2调节剂单用治疗的抗肿瘤免疫调节

SHP2调节剂单用不仅可以通过调控下游信号通路直接抑制肿瘤的生长增殖, 而且还可以通过改善免疫微环境间接发挥肿瘤抑制作用^[4]。按照结合模式, 目前用于肿瘤免疫领域的SHP2抑制剂可分为正构抑制剂和变构抑制剂。其中正构抑制剂主要有PHPS1, 变构抑制剂包括SHP099、RMC-4550、RMC-4630、TNO155、JAB-3068、JAB-3312、BBP398、HBI-2376和ICP-189^{[19-21, 23, 24, 61, 62]}。此外, SHP2激活剂trichomide A和fusaruside也表现出抗肿瘤免疫功能^{[27, 28]} (表 1)。

2.1.1 PHPS1

苯肼基吡唑啉酮磺酸盐1 (phenylhydrazonopyrazolone sulfonate 1, PHPS1)是一种特异性的SHP2正构抑制剂(IC₅₀ = 1 380 nmol·L^-1), 可通过与SHP2的PTP活性中心结合抑制酪氨酸磷酸酶的磷酸化, 阻断SHP2下游RAS-MAPK信号通路, 发挥抗肿瘤作用。除此之外, PHPS1也可以调控免疫微环境而发挥肿瘤免疫调节作用^[63]。SHP2是嗜酸性粒细胞分化的关键调节因子, 可促进嗜酸性粒细胞的形成, 而嗜酸性粒细胞可以浸润气道和肺组织, 从而引起过敏性哮喘。PHPS1可以抑制SHP2, 阻断嗜酸性粒细胞的分化, 减轻过敏性气道炎症^[64]。此外, PHPS1可抑制IL-8的高表达, 从而缓解吸烟诱导的各种炎症反应^[65]。PHPS1还可以使巨噬细胞向M2极化增多, 而向M1极化减少, 减轻不可分型流感嗜血杆菌(nontypeable haemophilus influenzae, NTHi) 感染期间的肺部炎症^{[61, 66]}。然而, 由于PTP催化位点的正电荷环境以及PTP催化域氨基酸序列的高度保守性, SHP2正构抑制剂的临床应用面临着缺乏选择性、生物利用性差等挑战^[67]。

2.1.2 SHP099

SHP099是由Novartis公司报道的首个高潜能、高选择性、可口服利用的小分子SHP2变构抑制剂(IC₅₀ = 70 nmol·L^-1)^[68]。SHP099可通过将SHP2稳定在自抑制构象而抑制SHP2的活性, 干扰RAS-ERK信号转导, 发挥抗肿瘤细胞增殖作用^[69]。SHP099还可以抑制不同酪氨酸激酶下游ERK的再激活, 减弱间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK) 或MEK抑制剂的耐药性, 发挥协同抗肿瘤效果^{[70, 71]}。此外, SHP099也可增强抗肿瘤免疫, 主要表现为分化决定簇8 (cluster of differentiation 8, CD8⁺) IFN-γ⁺ T细胞比例升高, 细胞毒性T细胞相关基因颗粒酶B (granzyme B, GZMB) 和穿孔素(perforin, PF) 表达上调, 从而降低肿瘤的大小、数量以及在体内的活跃程度^[62]。以上研究表明了SHP099在肿瘤免疫治疗领域的应用潜力, 但SHP099仍存在光毒性和心脏毒性的风险, 限制了临床应用的开展^{[67, 69]}。

2.1.3 RMC-4550

RMC-4550是由Revolution Medicine公司以SHP099为先导化合物合成的一种高潜能、高选择性的SHP2变构抑制剂(IC₅₀ = 0.58 nmol·L^-1)^[72]。与SHP099类似, RMC-4550也通过稳定SHP2的自抑制构象, 阻断RAS-ERK信号传导, 从而发挥抑癌作用^[73]。RMC-4550还可以调节免疫微环境, 使CD8⁺ T细胞浸润, 抑制CSF-1受体信号转导, 进一步选择性消耗M2型巨噬细胞, 通过CD8⁺ T细胞或IFN-γ机制增加M1型巨噬细胞数量, 激活体内的肿瘤免疫应答^[74]。值得注意的是, 研究表明RMC-4550在携带鼠类肉瘤滤过性毒菌致癌同源体B (V-raf murine sarcoma viral oncegene homolog B, BRAF) 3类突变、致癌RAS突变及神经纤维瘤病1型(neurofibromatosis type 1, NF1) 功能缺失突变的人类癌症模型中均发挥着有效的抗肿瘤作用^[73]。

2.1.4 RMC-4630

RMC-4630是由Revolution Medicine公司开发的一种RMC-4550衍生物, 是一种具有强效性和选择性的口服SHP2变构抑制剂^[60]。与RMC-4550作用相似, RMC-4630可抑制RAS信号传导, 增加T细胞浸润, 选择性消耗M2型巨噬细胞, 从而发挥肿瘤免疫效应。RMC-4630处理后可减少血液中单核细胞和单核样髓系抑制性细胞, 表明RMC-4630在先天和适应性抗肿瘤免疫治疗方面存在一定的潜力^[20]。此外, RMC-4630单药使用在晚期复发或难治性实体瘤、非小细胞肺癌和子宫癌等患者中均显示出抗肿瘤活性^[75]。

2.1.5 TNO155

TNO155是由Novartis公司在SHP099基础上优化获得的首个进入临床研究的高活性、高选择性且可口服利用的SHP2变构抑制剂(IC₅₀ = 11 nmol·L^-1)^[18]。SHP2与TNO155的共晶结构(PDB号: 7JVM) 显示: TNO155通过与SHP2的C-SH2/PTP结构域界面的隧道口袋处结合, 将SHP2锁定在自抑制的闭合构象中, 使其不能发挥去磷酸化作用^[4]。TNO155不仅可阻断由受体酪氨酸激酶(receptor tyrosine kinase, RTK) 介导的RAS-MAPK下游信号传导以及反馈途径的激活, 也可调控肿瘤微环境增强抗肿瘤免疫。TNO155可以有效阻断分化决定簇14 (cluster of differentiation 14, CD14⁺) 单核细胞的增殖, 增强细胞毒性T细胞的功能, 解除对巨噬细胞的免疫抑制作用, 增强PD-1阻断剂的疗效^{[19, 76]}。在BRAF突变结直肠癌中, TNO155可以增强其对BRAF和MEK抑制剂的敏感性, 提高药物疗效。此外, TNO155也可以增强KRAS^G12C抑制剂对KRAS^G12C肺癌和结直肠癌的疗效^[76]。

2.1.6 JAB-3068和JAB-3312

JAB-3068和JAB-3312分别是由Jacobio公司开发的第一代和第二代具有高选择性的SHP2变构抑制剂, 可以通过抑制SHP2介导的RTK-MAPK信号通路, 抑制肿瘤细胞的生长和增殖^[4]。除此之外, JAB-3068也可以阻断T细胞的PD-1通路, 增强CD8⁺ T细胞的杀伤功能, 并可以通过抑制肿瘤相关巨噬细胞(tumor-associated macrophage, TAM) 的功能调控肿瘤免疫微环境, 增强肿瘤免疫治疗的功效^[21]。JAB-3312则可以通过抑制SHP2进而阻断T细胞的PD-1通路和肿瘤细胞的KRAS通路, 具有肿瘤免疫和肿瘤靶向双重作用^[21]。JAB-3068主要用于治疗食管癌、头颈癌等转移性实体瘤, JAB-3312用于治疗结直肠癌、胰腺癌、非小细胞肺癌等各种实体瘤^[4]。2019年, JAB-3068和JAB-3312被美国食品药品监督管理局认定为治疗食道癌的孤儿药。不同的是JAB-3068主要用于单药疗法, 而JAB-3312倾向于联合用药。值得注意的是, 有研究指出JAB-3312与JAB-21822联合使用可以克服KRAS^G12C抑制剂的适应性耐药, 为KRAS^G12C抑制剂耐药患者提供了潜在的治疗希望^[77]。

2.1.7 BBP398

BBP398是由BridgeBio Pharma开发的一种高选择性、高潜能、可口服利用的小分子SHP2变构抑制剂(IC₅₀ = 16 nmol·L^-1)^[17]。BBP398不仅可以作为单一药物发挥作用, 还可以与其他MAPK信号通路抑制剂联合使用, 发挥协同抑制肿瘤生长的功能^[78]。目前BBP398与PD-1抗体联用在肿瘤免疫领域的应用已被报道, 但BBP398单药是否具备抗肿瘤免疫功能仍有待研究^[79]。

2.1.8 HBI-2376

作为一种口服生物可利用的选择性SHP2变构抑制剂, HBI-2376目前正用于开展针对含KRAS或EGFR突变的实体瘤如非小细胞肺癌和结肠癌患者的临床研究。除了调控肿瘤细胞生长增殖外, HBI-2376还可以通过调控肿瘤免疫微环境中的免疫浸润细胞活性如抑制M2型巨噬细胞的浸润而抑制肿瘤生长。与SHP099和RMC-4550相比, HBI-2376无论是单药还是与PD-1联用的抗肿瘤增殖效果均更佳。鉴于此, HBI-2376已经获得美国食品药品监督管理局批准开展针对非小细胞肺癌或结直肠癌患者的临床研究^[23]。

2.1.9 ICP-189

ICP-189是一种由InnoCare Pharma自主研发的高选择性口服SHP2变构抑制剂, 旨在通过单药疗法或联合疗法为肺癌、头颈癌及消化道肿瘤等实体瘤患者提供新的临床治疗方案。ICP-189能够特异性地与SHP2的闭合构象结合, 抑制多条RTK介导信号通路的异常激活, 从而抑制肿瘤细胞的生长^[24]。临床研究表明ICP-189在各种异种移植模型中表现出显著的抗肿瘤作用。除此之外, ICP-189还可以通过抑制SHP2恢复Th1免疫功能, 活化T细胞, 进而调节肿瘤免疫微环境^[24]。

2.1.10 Trichomide A

Trichomide A目前已被鉴定为具有高度选择性的SHP2激活剂^[18]。Trichomide A可以有效抑制活化T细胞的增殖和促炎细胞因子的产生。在Con A激活的T细胞中, trichomide A可通过诱导SHP2的酪氨酸磷酸化, 抑制下游AKT和STAT3信号传导, 以SHP2依赖的方式对活化的T细胞发挥免疫抑制效应^[27]。Trichomide A可以用于改善苦基氯(picryl chloride, PCl) 诱导的小鼠接触性皮炎, 而利用PHPS1或在T细胞中条件性敲除SHP2则可显著逆转trichomide A的这种作用, 暗示了trichomide A在治疗免疫相关皮肤病方面的应用潜力^[27]。

2.1.11 Fusaruside

Fusaruside是一种天然脑苷脂化合物, 可以激活SHP2的磷酸酶非依赖性活性, 并以剂量依赖性和时间依赖性的方式选择性地抑制STAT1的磷酸化^{[80, 81]}。磷酸化的SHP2与胞浆中非磷酸化的STAT1选择性结合可阻止其向IFN-γR募集, 进而抑制STAT1/T-bet信号的传导^[81]。在三硝基苯磺酸(trinitro-benzene-sulfonic acid, TNBS) 诱导的小鼠结肠炎模型中, fusaruside可以抑制肠系膜淋巴结及肠组织中CD4⁺ T细胞STAT1的活化, 阻断肠组织中T-bet的表达及血清中Th1因子IFN-γ的分泌。以上研究为fusaruside改善Th1型肠道炎症提供了理论依据^{[18, 81]}。此外, fusaruside可以通过下调肝脏中的STAT1活化和T-bet表达, 以及上调STAT3活化和B细胞淋巴瘤-X_L (B-cell lymphoma-extra large, Bcl-X_L) 表达的新型调节机制, 重建STAT1和STAT3信号转导的平衡, 抑制T细胞介导的肝损伤能力, 表明了fusaruside在治疗T细胞介导的人类肝脏疾病中的应用前景^[28]。

2.2 SHP2调节剂联合用药的抗肿瘤免疫调控

基于SHP2在肿瘤靶向与免疫调控中的双重功能, SHP2调节剂与其他上下游信号通路抑制剂的联用可发挥协同肿瘤免疫调控功能, 克服获得性耐药, 进一步提高药物疗效^{[17, 21]}。截止目前, 诺华、加科思、基因泰克等企业均已积极开展了SHP2变构抑制剂与PD-1/PD-L1阻断剂联合用药的临床治疗研究。此外, SHP2抑制剂与其他激酶靶向药物的联合也为肿瘤免疫治疗带来了新的曙光^{[82, 83]}。

2.2.1 SHP2抑制剂与免疫检查点阻断剂的联用

在PD-1/PD-L1信号通路的调控中, SHP2抑制剂一方面可以阻断PD-1对SHP2的招募, 促进T细胞受体下游信号的传导, 另一方面可以使CD28介导的PI3K激活, 从而传递共刺激信号, 恢复T细胞的功能^{[11, 84]}。此外, SHP2抑制剂可以改善ZAP70与分化决定簇3ζ链(cluster of differentiation 3 zeta, CD3ζ) 上免疫受体酪氨酸激活基序的结合, 促进下游信号传导, 有利于TCR介导的IL-2合成, 从而促进T细胞的增殖^[10]。鉴于PD-1阻断剂专门针对耗竭性T细胞, 并对各种靶向治疗表现出耐受性, 因此SHP2与PD-1抑制剂联用在恢复T细胞免疫应答中至关重要。SHP2抑制剂与PD-1阻断剂联合用药可以恢复Th1免疫, 激活T细胞, 从而逆转肿瘤微环境中的免疫抑制, 发挥抗肿瘤作用^[47]。除SHP099外, 目前已有包括TNO155、RMC-4630、ERAS-601、JAB-3068、JAB-3312、BBP398、GDC-1971和BR790在内的8种SHP2变构抑制剂联合PD-1/PD-L1抗体的临床研究正在进行中(表 2)^{[25, 62, 76]}。

在小鼠MC-38和CT-26结肠癌异种移植瘤模型中, SHP099单药治疗时可增强抗肿瘤免疫, CD8⁺IFN-γ⁺ T细胞比例升高, 细胞毒性T细胞相关基因上调, 从而降低了肿瘤负荷; 与之相比, SHP099联合PD-1阻断剂RMP1-14可协同激活T细胞, 诱导肿瘤细胞凋亡, 并使细胞毒性T细胞产生的细胞因子急剧增加, 能更好地控制肿瘤生长。因此, 二者的联合治疗在调节肿瘤生长方面表现出比单药更强的治疗效果, 将是一种潜在的强有力的癌症治疗策略^[62]。TNO155与PD-1抗体联合也呈现出较好的抗肿瘤活性。在MC-38和CT-26同源结肠肿瘤模型中, PD-1阻断剂α-PD-1对M2型肿瘤相关巨噬细胞没有抑制作用, 但TNO155联合PD-1抗体可显著抑制肿瘤相关巨噬细胞。然而TNO155与PD-1抗体联合用药对M2巨噬细胞减少的协同作用机制尚不清楚, 仍需要进一步探索^[76]。2019年6月27日, 一项Ib期、多中心、剂量递增/剂量扩增型临床研究在成年晚期实体瘤患者中开展, 用于表征TNO155联合PD-1抗体司帕他利单抗(spartalizumab) 的安全性、耐受性、药物代谢动力学、药物效应动力学和初步疗效, 并确定联合用药的最大耐受剂量和/或推荐方案(NCT04000529)^[85]。2020年6月5日, 一项RMC-4630与帕博利珠单抗(pembrolizumab) 联合用药的Ⅰ期多中心临床研究正式启动, 旨在评估二者联用在实体肿瘤患者中的安全性、联合用药的最大耐受剂量和临床Ⅱ期推荐剂量(NCT04418661)^[86]。2020年12月17日, 一项Ⅰ/Ⅰb期、多中心、剂量递增/剂量扩增型临床研究启动, 评估ERAS-601单药治疗和联合帕博利珠单抗在晚期或转移性实体瘤患者中的最大耐受剂量和/或推荐剂量(NCT04670679)^[25]。JAB-3068也可与PD-1/PD-L1抗体联用治疗对PD-1/PD-L1抗体无应答的肿瘤^[21]。2021年1月22日, 一项多中心、剂量递增/剂量扩增型的临床Ⅰb/Ⅱa期研究启动, 评估JAB-3068联合PD-1阻断剂特瑞普利单抗(toripalimab) 在晚期实体瘤患者中的安全性、耐受性、药物代谢动力学和抗肿瘤活性, 并确定临床Ⅱ期推荐剂量(NCT04721223)^[87]。同时, 一项评估JAB-3312联合PD-1抗体帕博利珠单抗的Ⅰ/Ⅱa期临床试验也于2021年启动(NCT04720976)。此外, BBP398与PD-1抗体联用也为携带KRAS突变的肿瘤患者提供了治疗希望, 但具体作用机制还有待进一步探索^[79]。2022年5月16日, 一项关于BBP398与PD-1抗体纳武单抗(nivolumab) 联合治疗的临床Ⅰ期研究启动, 评估两者联用对标准方案治疗失败的携带KRAS突变的非小细胞肺癌晚期患者的安全性、耐受性、临床Ⅱ期推荐剂量和抗肿瘤活性(NCT05375084)^[88]。2022年8月4日, 一项旨在评估GDC-1971联合PD-L1抗体阿特珠单抗(atezolizumab)治疗局部晚期或转移性实体瘤患者的安全性、药代动力学和抗肿瘤活性的Ib期临床研究正式启动(NCT05487235)^[25]。2022年8月18日, 一项Ⅰ/Ⅱa期、多中心的临床研究在晚期实体瘤患者中进行, 用于评估SHP2抑制剂BR790联合PD-1抑制剂替雷利珠(tislelizumab) 的安全性、耐受性、药物代谢动力学、药物效应动力学和初步抗肿瘤活性(NCT05505877)。

SHP2抑制剂与免疫检查点阻断剂PD-1/PD-L1联用是癌症治疗漫漫长征路上的一种极具前景的策略, 肿瘤靶向治疗与免疫治疗的双重结合将为肿瘤患者带来曙光。然而, SHP2抑制剂与其他免疫检查点阻断剂如T细胞激活抑制物免疫球蛋白可变区结构域(V-domain immunoglobulin suppressor of T cell activation, VISTA)、CTLA-4、CSF-1R、淋巴细胞活化基因3 (lymphocyte activation gene-3, LAG-3)、T细胞免疫球蛋白黏液素3 (T cells immunoglobulin mucin-3, TIM-3)、TIGHT、SIRPα、BTLA、白细胞免疫球蛋白样受体(the leukocyte immunoglobulin-like receptor subfamily B, LILRB) 和Siglec-7等的联用研究却鲜有报道, SHP2在其他免疫细胞及免疫检查点中的作用机制也有待深入研究。

2.2.2 SHP2抑制剂与激酶靶向药物的联用

SHP2及上下游信号分子的致癌突变可能会阻碍SHP2调节剂的疗效, 获得性耐药的出现对精准治疗带来了巨大的挑战。SHP2抑制剂与其他激酶靶向药物的联合应用为提高疗效和克服耐药性提供了一种新的治疗策略^[17]。SHP2抑制剂与激酶靶向药物如KRAS^G12C抑制剂和细胞周期蛋白依赖性激酶4/6 (cyclin-dependent kinase 4 and 6, CDK4/6) 抑制剂的联合治疗可通过阻止RAS-MAPK信号通路, 抑制肿瘤细胞的生长和免疫细胞的激活, 逆转肿瘤微环境中的免疫抑制, 进而发挥强大的肿瘤杀伤作用(表 3)^{[82, 83]}。

在异种移植KRAS^G12C突变型胰腺导管腺癌(pancreatic ductal adenocarcinoma, PDAC) 和非小细胞肺癌模型中, SHP099和KRAS^G12C抑制剂ARS1620联用可导致免疫微环境中肿瘤部位特异性的变化, 减少髓样抑制细胞(myeloid suppressor cells, MSCs), 增加CD8⁺ T细胞, 提高肿瘤对PD-1阻断剂的敏感性。而且当二者与PD-1阻断剂联合使用时, 可以进一步改善KRAS^G12C肿瘤的治疗效果^[82]。因此, 由SHP2、KRAS^G12C和PD-1抑制剂组成的三联疗法为非小细胞肺癌的治疗提供了潜在的治疗策略。此外, RMC-4550作为单药使用时可激活T细胞并消耗M2型巨噬细胞, 产生适度的肿瘤抑制作用。但当其与CDK4/6抑制剂阿贝西利(abemaciclib) 联合治疗时能够增强抗肿瘤免疫, 且在小鼠乳腺癌模型中表现出良好的耐受性, 发挥协同治疗效果^[83]。然而, SHP2抑制剂与EGFR抑制剂、BRAF抑制剂、MEK抑制剂、ERK抑制剂等其他激酶靶向药物联合应用是否可以调控肿瘤免疫效应仍有待进一步研究。

3 结语与展望

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SHP2在肿瘤细胞的发生与发展过程中不仅可以发挥促癌作用, 也可发挥抑癌作用。SHP2是癌症治疗的潜在靶点, 其调节剂的开发已成为当前肿瘤靶向药物研究的热点^{[4, 18]}。近年来随着肿瘤免疫治疗的不断深入, SHP2调节剂在肿瘤免疫领域的应用也开启了一个全新的篇章。SHP2可参与调控多个免疫检查点信号通路并介导免疫逃逸的发生, 因此开发SHP2调节剂对于增强肿瘤免疫应答尤为重要。SHP2调节剂不仅可以通过单药治疗调节肿瘤微环境而发挥抗肿瘤免疫作用, 而且还可与免疫检查点阻断剂或激酶靶向药物联用改善免疫微环境, 协同发挥抗肿瘤效果^{[62, 82, 83]}。迄今为止, 靶向SHP2的正构抑制剂、变构抑制剂和激活剂在肿瘤免疫领域的应用均有报道, 其中靶向SHP2独特变构调控机制的变构抑制剂在肿瘤免疫调控中发挥着显著的优势^[17]。值得一提的是, SHP2变构抑制剂的单用及其与免疫检查点阻断剂联用的临床试验备受关注^[16]。然而, SHP2调节剂在肿瘤免疫调控中的研究仍存在许多亟待解决的问题。由于SHP2磷酸酶活性位点的高度保守性和极性带电环境, 靶向磷酸酶催化结构域的正构抑制剂存在选择性低、透膜性差和口服生物利用度低等不足, 限制了SHP2正构抑制剂的临床应用; 变构抑制剂由于其固有的非特异性和可能的脱靶效应, 使得开发更有效和特异性的抑制剂迫在眉睫, 此外鉴于突变可能破坏SHP2结构域的完整性, 进而导致抑制剂的耐药性, 因此SHP2变构抑制剂与上下游以及旁路信号分子抑制剂联用可能是一条新途径; 值得一提的是, SHP2激活剂是把双刃剑, 其可用于治疗SHP2失活相关的疾病, 然而过度激活SHP2也可能具有潜在的致癌风险, 因此SHP2的激活状态应该被精确调节^{[18, 89]}。除了PD-1/PD-L1外, SHP2变构抑制剂与其他免疫检查点阻断剂如VISTA、CTLA-4、CSF-1R、LAG-3、TIM-3、TIGHT、SIRPα、BTLA、LILRB和Siglec-7的联用机制仍有待进一步深入研究^[16]。针对SHP2正构抑制剂以及激活剂的联合治疗鲜有报道。此外, SHP2抑制剂与激酶靶向药物联用调控肿瘤免疫的分子机制仍需继续研究, 为二者联用的临床应用奠定基础^{[82, 83]}。综上所述, 靶向SHP2是一种有前景的肿瘤免疫治疗方法, 其不仅可以通过靶向RAS、PI3K等信号通路抑制肿瘤生长, 还能增强抗肿瘤免疫功能, 从而达到靶向治疗与免疫治疗相结合的双重功效^{[62, 69]}。此外, SHP2调节剂与免疫检查点阻断剂联用是一种有潜力的肿瘤免疫治疗策略, 有望为不同癌症患者提供有效的肿瘤治疗方案^[19]。

作者贡献: 杨欣语、尚佳文和于海云负责初稿撰写、插图和表格绘制; 宋宜辉和余斌负责文章构思布局、论文指导和修改。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(31900875)
河南省优势学科培育联合基金(22610013)
教育部“春晖计划”合作科研项目(HZKY20220280)
郑州大学大学生创新创业训练计划项目(2023CXCY711)

参考文献

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2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2023-0628

接收时间：2023-05-13
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2023-05-13
修回日期：2023-06-29

基金

国家自然科学基金资助项目(31900875)

河南省优势学科培育联合基金(22610013)

教育部“春晖计划”合作科研项目(HZKY20220280)

郑州大学大学生创新创业训练计划项目(2023CXCY711)

作者信息

1.郑州大学药学院药物研究院, 河南郑州 450001

2.药物关键制备技术教育部重点实验室, 河南郑州 450001

通讯作者:

*宋宜辉, Tel: 86-371-67781908, E-mail: songyihui@zzu.edu.cn;

余斌, E-mail: yubin@zzu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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TxT

Drug name	Chemical structure	IC₅₀/nmol·L^-1	Mechanism	Indication	Clinical status
PHPS1		1 380	It alleviates the pulmonary inflammatory response by modulating immune cells	Pulmonary inflammation	Preclinical
SHP099		70	It promotes cytokine/granule production by cytotoxic T cells to exert tumor immunomodulatory effects	Colon cancer	Preclinical
RMC-4550		0.58	It directly impacts the survival and function of suppressive monocytic immune cells	Colon cancer	Preclinical
RMC-4630	/	/	It increases T cell infiltration, selectively depletes M2 type macrophages	Non-small cell lung cancer	Phase Ⅱ
TNO155		11	It can inhibit immune-suppressive macrophages	Ovarian cancer, breast cancer, colorectal cancer, colon cancer	Phase Ⅰ/Ⅱ
JAB-3068		/	It can block the PD-1 pathway of T cells, enhance the ability of CD8⁺ T cells, and inhibit TAM function	Advanced or metastatic solid tumors	Phase Ⅱ
JAB-3312	/	/	Phase Ⅰ/Ⅱ
BBP398		16	It can inhibit tumor growth by blocking RAS-ERK signaling and can be combined with PD-1 antibodies	Advanced solid tumors with a KRAS mutation	Phase Ⅰ
HBI-2376		/	It can inhibit tumor growth by inducing the activity of immune infiltrating cells	Solid tumors with KRAS or EGFR mutations	Phase Ⅰ
ICP-189	/	/	It can restore Th1 immune function and activate T cells, thereby triggering the immune response	Solid tumors such as lung cancer, head and neck cancer and gastrointestinal cancer	Phase Ⅰ
Trichomide A		/	It can effectively inhibit the proliferation of activated T cells and the production of pro-inflammatory cytokines	Immune-related skin diseases	Preclinical
Fusaruside		/	It can inhibit STAT1/T-bet signaling and rebuild the balance of STAT1 and STAT3 signaling	Colitis, hepatitis	Preclinical

Drug name

Chemical structure

IC₅₀/nmol·L^-1

Mechanism

Indication

Clinical status

PHPS1

1 380

It alleviates the pulmonary inflammatory response by modulating immune cells

Pulmonary inflammation

Preclinical

SHP099

It promotes cytokine/granule production by cytotoxic T cells to exert tumor immunomodulatory effects

Colon cancer

Preclinical

RMC-4550

0.58

It directly impacts the survival and function of suppressive monocytic immune cells

Colon cancer

Preclinical

RMC-4630

It increases T cell infiltration, selectively depletes M2 type macrophages

Non-small cell lung cancer

Phase Ⅱ

TNO155

It can inhibit immune-suppressive macrophages

Ovarian cancer, breast cancer, colorectal cancer, colon cancer

Phase Ⅰ/Ⅱ

JAB-3068

It can block the PD-1 pathway of T cells, enhance the ability of CD8⁺ T cells, and inhibit TAM function

Advanced or metastatic solid tumors

Phase Ⅱ

JAB-3312

Phase Ⅰ/Ⅱ

BBP398

It can inhibit tumor growth by blocking RAS-ERK signaling and can be combined with PD-1 antibodies

Advanced solid tumors with a KRAS mutation

Phase Ⅰ

HBI-2376

It can inhibit tumor growth by inducing the activity of immune infiltrating cells

Solid tumors with KRAS or EGFR mutations

Phase Ⅰ

ICP-189

It can restore Th1 immune function and activate T cells, thereby triggering the immune response

Solid tumors such as lung cancer, head and neck cancer and gastrointestinal cancer

Phase Ⅰ

Trichomide A

It can effectively inhibit the proliferation of activated T cells and the production of pro-inflammatory cytokines

Immune-related skin diseases

Preclinical

Fusaruside

It can inhibit STAT1/T-bet signaling and rebuild the balance of STAT1 and STAT3 signaling

Colitis, hepatitis

Preclinical

Drug name	Chemical structure	Corporation	PD-1/PD-L1 antibody	Indication	Clinical status
SHP099		Novartis	RMP1-14	Colon cancer	Preclinical
TNO155		Novartis	Spartalizumab	Non-small cell lung carcinoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastrointestinal stromal tumors, colorectal cancer	Phase Ⅰ
RMC-4630	/	Revolution Medicine	Pembrolizumab	Metastatic lung cancer	Phase Ⅰ/Ⅱ
ERAS-601	/	Erasca	Pembrolizumab	HPV negative advanced or metastatic head and neck squamous cell carcinoma or non-small cell lung cancer	Phase Ⅰ
JAB-3068		Jacobio	Toripalimab	Esophageal squamous cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma	Phase Ⅰ/Ⅱ
JAB-3312	/	Jacobio	Pembrolizumab	Non-small cell lung cancer	Phase Ⅰ/Ⅱ
BBP398		Navire Pharma	Nivolumab	Advanced non-small cell lung cancer with a KRAS mutation	Phase Ⅰ
GDC-1971		Genentech	Atezolizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma	Phase Ⅰ
BR790	/	Gopherwood Biotech	Tislelizumab	Non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma	Phase Ⅰ/Ⅱ

Drug name

Chemical structure

Corporation

PD-1/PD-L1 antibody

Indication

Clinical status

SHP099

Novartis

RMP1-14

Colon cancer

Preclinical

TNO155

Novartis

Spartalizumab

Non-small cell lung carcinoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, gastrointestinal stromal tumors, colorectal cancer

Phase Ⅰ

RMC-4630

Revolution Medicine

Pembrolizumab

Metastatic lung cancer

Phase Ⅰ/Ⅱ

ERAS-601

Erasca

Pembrolizumab

HPV negative advanced or metastatic head and neck squamous cell carcinoma or non-small cell lung cancer

Phase Ⅰ

JAB-3068

Jacobio

Toripalimab

Esophageal squamous cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma

Phase Ⅰ/Ⅱ

JAB-3312

Jacobio

Pembrolizumab

Non-small cell lung cancer

Phase Ⅰ/Ⅱ

BBP398

Navire Pharma

Nivolumab

Advanced non-small cell lung cancer with a KRAS mutation

Phase Ⅰ

GDC-1971

Genentech

Atezolizumab

Non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma

Phase Ⅰ

BR790

Gopherwood Biotech

Tislelizumab

Non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma

Phase Ⅰ/Ⅱ

Drug name	Corporation	Kinase targeted agent	Indication	Clinical status
SHP099	Novartis	ARS1620	KRAS^G12C-mutant PDAC and NSCLC	Preclinical
RMC-4550	Revolution Medicine	Abemaciclib	Breast cancer	Preclinical

Drug name

Corporation

Kinase targeted agent

Indication

Clinical status

SHP099

Novartis

ARS1620

KRAS^G12C-mutant PDAC and NSCLC

Preclinical

RMC-4550

Revolution Medicine

Abemaciclib

Breast cancer

Preclinical