靶向肿瘤相关巨噬细胞增强结直肠癌免疫检查点抑制剂疗效的潜在策略

doi:10.3760/cma.j.cn371439-20230725-00129

摘要/Abstract

摘要：

肿瘤相关巨噬细胞（TAM）在肿瘤的进展与转移中起着关键性作用，它们的特性高度依赖于肿瘤微环境（TME）的信号刺激。TAM作为肿瘤相关炎症的主要参与者，与多种实体肿瘤的预后相关。免疫检查点抑制剂（ICI）可极大地改善微卫星不稳定或错配修复缺陷结直肠癌（CRC）患者的生存预后。然而，ICI作为单一疗法在绝大多数的CRC患者中疗效受限。尽管TAM的确切功能尚未完全阐明，但以TAM为靶点的治疗策略能明显改善CRC患者的ICI疗效，TAM作为CRC预后的预测标志物也显示出重要价值。

关键词: 结直肠肿瘤, 肿瘤微环境, 肿瘤相关巨噬细胞, 免疫检查点抑制剂

Abstract:

Tumor-associated macrophage （TAM） plays a key role in tumor progression and metastasis，and their properties are highly dependent on signaling stimuli in the tumor microenvironment（TME）. Moreover，TAM，as a major player in tumor-related inflammation，is associated with the prognosis of multiple solid tumors. Immune checkpoint inhibitor （ICI） was found to significantly improve the survival prognosis of patients with microsatellite instability/mismatched repair deficient colorectal cancer. However，the efficacy of ICI as monotherapy is limited in the vast majority of CRC patients. Although the exact functions of TAM have not been fully elucidated，targeting TAM as a therapeutic strategy significantly enhances the efficacy of ICI in CRC，and TAM also demonstrates important value as predictive biomarkers for CRC prognosis.

Key words: Colorectal neoplasms, Tumor microenvironment, Tumor-associated macrophages, Immune checkpoint inhibitors

陶红, 殷红, 罗宏, 陶佳瑜. 靶向肿瘤相关巨噬细胞增强结直肠癌免疫检查点抑制剂疗效的潜在策略[J]. 国际肿瘤学杂志, 2023, 50(11): 683-687.

Tao Hong, Yin Hong, Luo Hong, Tao Jiayu. Potential strategies for targeting tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors for colorectal cancer[J]. Journal of International Oncology, 2023, 50(11): 683-687.

参考文献 35

[1]	Katsaounou K, Nicolaou E, Vogazianos P, et al. Colon cancer: from epidemiology to prevention[J]. Metabolites, 2022, 12(6): 499. DOI: 10.3390/metabo12060499.
[2]	Li J, Chen D, Shen M. Tumor microenvironment shapes colorectal cancer progression, metastasis, and treatment responses[J]. Front Med (Lausanne), 2022, 9: 869010. DOI: 10.3389/fmed.2022.869010.
[3]	Chen Y, Song Y, Du W, et al. Tumor-associated macrophages: an accomplice in solid tumor progression[J]. J Biomed Sci, 2019, 26(1): 78. DOI: 10.1186/s12929-019-0568-z. pmid: 31629410
[4]	Li J, Li L, Li Y, et al. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis[J]. Int J Colorectal Dis, 2020, 35(7): 1203-1210. DOI: 10.1007/s00384-020-03593-z. pmid: 32303831
[5]	Yin Y, Liu B, Cao Y, et al. Colorectal cancer-derived small extracellular vesicles promote tumor immune evasion by upregulating PD-L1 expression in tumor-associated macrophages[J]. Adv Sci (Weinh), 2022, 9(9): 2102620. DOI: 10.1002/advs.202102620.
[6]	Li C, Xu X, Wei S, et al. Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer[J]. J Immunother Cancer, 2021, 9(1): e001341. DOI: 10.1136/jitc-2020-001341.
[7]	Boutilier AJ, Elsawa SF. Macrophage polarization states in the tumor microenvironment[J]. Int J Mol Sci, 2021, 22(13): 6995. DOI: 10.3390/ijms22136995.
[8]	Wu K, Lin K, Li X, et al. Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment[J]. Front Immunol, 2020, 11: 1731. DOI: 10.3389/fimmu.2020.01731. pmid: 32849616
[9]	Zhou J, Tang Z, Gao S, et al. Tumor-associated macrophages: recent insights and therapies[J]. Front Oncol, 2020, 10: 188. DOI: 10.3389/fonc.2020.00188. pmid: 32161718
[10]	Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy[J]. Immunity, 2014, 41(1): 49-61. DOI: 10.1016/j.immuni.2014.06.010. pmid: 25035953
[11]	Pan Y, Yu Y, Wang X, et al. Tumor-associated macrophages in tumor immunity[J]. Front Immunol, 2020, 11: 583084. DOI: 10.3389/fimmu.2020.583084.
[12]	Jeong H, Kim S, Hong BJ, et al. Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis[J]. Cancer Res, 2019, 79(4): 795-806. DOI: 10.1158/0008-5472.CAN-18-2545. pmid: 30610087
[13]	Lan Q, Lai W, Zeng Y, et al. CCL26 participates in the PRL-3-induced promotion of colorectal cancer invasion by stimulating tumor-associated macrophage infiltration[J]. Mol Cancer Ther, 2018, 17(1): 276-289. DOI: 10.1158/1535-7163.MCT-17-0507. pmid: 29051319
[14]	Liang ZX, Liu HS, Wang FW, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization[J]. Cell Death Dis, 2019, 10(11): 829. DOI: 10.1038/s41419-019-2077-0.
[15]	Huang C, Ou R, Chen X, et al. Tumor cell-derived SPON2 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by activating PYK2 in CRC[J]. J Exp Clin Cancer Res, 2021, 40(1): 304. DOI: 10.1186/s13046-021-02108-0. pmid: 34583750
[16]	Zhong Q, Fang Y, Lai Q, et al. CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling[J]. J Exp Clin Cancer Res, 2020, 39(1): 132. DOI: 10.1186/s13046-020-01637-4. pmid: 32653013
[17]	Liu C, Zhang W, Wang J, et al. Tumor-associated macrophage-derived transforming growth factor-β promotes colorectal cancer progression through HIF1-TRIB3 signaling[J]. Cancer Sci, 2021, 112(10): 4198-4207. DOI: 10.1111/cas.15101.
[18]	Li X, Liu R, Su X, et al. Harnessing tumor-associated macrophages as aids for cancer immunotherapy[J]. Mol Cancer, 2019, 18(1): 177. DOI: 10.1186/s12943-019-1102-3. pmid: 31805946
[19]	Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer[J]. Nat Rev Drug Discov, 2018, 17(12): 887-904. DOI: 10.1038/nrd.2018.169. pmid: 30361552
[20]	Chun E, Lavoie S, Michaud M, et al. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function[J]. Cell Rep, 2015, 12(2): 244-257. DOI: 10.1016/j.celrep.2015.06.024. pmid: 26146082
[21]	Tu MM, Abdel-Hafiz HA, Jones RT, et al. Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy[J]. Commun Biol, 2020, 3(1): 720. DOI: 10.1038/s42003-020-01441-y. pmid: 33247183
[22]	Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models[J]. Cancer Res, 2014, 74(18): 5057-5069. DOI: 10.1158/0008-5472.CAN-13-3723. pmid: 25082815
[23]	Cassier PA, Garin G, Eberst L, et al. MEDIPLEX: a phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC)[J]. J Clin Oncol, 2019, 37(15 suppl): 2579. DOI: 10.1200/JCO.2019.37.15_suppl.2579.
[24]	Haag GM, Springfeld C, Grün B, et al. Pembrolizumab and maraviroc in refractory mismatch repair proficient/microsatellite-stable metastatic colorectal cancer-the PICCASSO phase I trial[J]. Eur J Cancer, 2022, 167: 112-122. DOI: 10.1016/j.ejca.2022.03.017.
[25]	De Henau O, Rausch M, Winkler D, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells[J]. Nature, 2016, 539(7629): 443-447. DOI: 10.1038/nature20554.
[26]	Heller S, Glaeske S, Gluske K, et al. Pan-PI3K inhibition with copanlisib overcomes Treg- and M2-TAM-mediated immune suppression and promotes anti-tumor immune responses[J]. Clin Exp Med, 2023, 23(8): 5445-5461. doi: 10.1007/s10238-023-01227-6
[27]	Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis[J]. Nature, 2018, 554(7693):538-543. DOI: 10.1038/nature 25492.
[28]	Zha H, Wang X, Zhu Y, et al. Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modula-ting tumor-associated macrophages[J]. Cancer Immunol Res, 2019, 7(2): 193-207. DOI: 10.1158/2326-6066.CIR-18-0272.
[29]	Wen ZF, Liu H, Gao R, et al. Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1[J]. J Immunother Cancer, 2018, 6(1): 151. DOI: 10.1186/s40425-018-0452-5.
[30]	Kou Y, Li Z, Sun Q, et al. Prognostic value and predictive biomarkers of phenotypes of tumour-associated macrophages in colorectal cancer[J]. Scand J Immunol, 2022, 95(4): e13137. DOI: 10.1111/sji.13137.
[31]	Xu G, Jiang L, Ye C, et al. The ratio of CD86⁺/CD163⁺ macrophages predicts postoperative recurrence in stage Ⅱ-Ⅲ colorectal cancer[J]. Front Immunol, 2021, 12:724429. DOI: 10.3389/fimmu.2021.724429.
[32]	Zhao Y, Ge X, Xu X, et al. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer[J]. J Cancer Res Clin Oncol, 2019, 145(12): 3005-3019. DOI: 10.1007/s00432-019-03041-8. pmid: 31650222
[33]	Cavnar MJ, Turcotte S, Katz SC, et al. Tumor-associated macrophage infiltration in colorectal cancer liver metastases is associated with better outcome[J]. Ann Surg Oncol, 2017, 24(7): 1835-1842. DOI: 10.1245/s10434-017-5812-8. pmid: 28213791
[34]	Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity[J]. Nature, 2017, 545(7655): 495-499. DOI: 10.1038/nature22396.
[35]	Bortolomeazzi M, Keddar MR, Montorsi L, et al. Immunogenomics of colorectal cancer response to checkpoint blockade: analysis of the KEYNOTE 177 trial and validation cohorts[J]. Gastroenterology, 2021, 161(4): 1179-1193. DOI: 10.1053/j.gastro.2021.06.064. pmid: 34197832