The CX3CL1-CX3CR1 chemokine axis can contribute to tumor immune evasion and blockade with a novel CX3CR1 monoclonal antibody enhances response to anti-PD-1 immunotherapy.
The CX3CL1-CX3CR1 chemokine axis can contribute to tumor immune evasion and blockade with a novel CX3CR1 monoclonal antibody enhances response to anti-PD-1 immunotherapy.
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DOI：
10.3389/fimmu.2023.1237715
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发表时间：
2023
影响因子：
7.3
通讯作者：
Freeman, Gordon J.
中科院分区：
文献类型：
--
作者：
Chaudhri, Apoorvi;Bu, Xia;Wang, Yunfei;Gomez, Michael;Torchia, James A.;Hua, Ping;Hung, Shao-Hsi;Davies, Michael A.;Lizee, Gregory A.;von Andrian, Ulrich;Hwu, Patrick;Freeman, Gordon J.
在肿瘤微环境中分泌的CX 3CL 1充当化学引诱物，在表达CX 3CR 1的癌细胞的转移中起关键作用。CX 3CR 1可以在癌症和免疫抑制性骨髓细胞中表达，以促进它们的迁移。我们制备了一种新的抗小鼠CX 3CR 1的单克隆抗体，该抗体与CX 3CR 1结合并阻断CX 3CL 1-CX 3CR 1相互作用。我们接下来探索了由CX 3CL 1-CX 3CR 1轴实施的免疫逃避策略，并发现它在癌细胞中启动抗性程序，导致1）促进肿瘤细胞迁移，2）分泌可溶性介质以产生促转移小生境，3）分泌可溶性介质以吸引骨髓群体，以及4）产生肿瘤炎性小体。CX 3CR 1单克隆抗体减少肿瘤细胞的迁移，并减少肿瘤细胞分泌免疫抑制性可溶性介质。与抗PD-1免疫疗法联合，这种CX 3CR 1单克隆抗体通过减少促肿瘤骨髓细胞群来提高免疫活性小鼠结肠癌模型的存活率。因此，该轴参与对抗PD-1免疫疗法的抗性机制，并且组合疗法可以克服对抗PD-1的部分抗性机制。
CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.
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