LAG3 阻断剂与微波消融联合促进 CD8 T 细胞介导的抗肿瘤免疫。
LAG3 blockade coordinates with microwave ablation to promote CD8 T cell-mediated anti-tumor immunity.
机构信息
Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu Province, China.
Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
出版信息
J Transl Med. 2022 Sep 30;20(1):433. doi: 10.1186/s12967-022-03646-7.
BACKGROUND
The immune checkpoint inhibitors (ICIs) combined with other therapeutic strategies have shown exciting results in various malignancies, and ICIs have now become the gold standard for current cancer treatment. In several preclinical and clinical investigations, ablation coupled with immunotherapy has proved to be quite effective. Our previous studies have shown that ablation coupled with ICI is a potential anti-cancer regimen for colorectal cancer liver metastases (CRLM). Furthermore, we have reported that following microwave ablation (MWA), the expression of LAG3 is up-regulated in tumor microenvironment (TME), indicating that LAG3 is implicated in the regulation of immunosuppressive immune response, and combination therapy of MWA and LAG3 blockade can serve as a promising therapeutic strategy against cancer.
METHODS
The expression of LAG3 was investigated in this study utilizing a preclinical mouse model treated with MWA. Moreover, we monitored the tumor development and survival in mice to assess the anti-cancer effects of MWA alone or in combination with LAG3 blockade. Flow cytometry was also used to phenotype the tumor-infiltrating lymphocytes (TILs) and CD8 T cell effector molecules. We finally analyzed the single-cell RNA sequencing (scRNA-seq) data of infiltrating CD45 immune cells in the tumors from the MWA alone and MWA combined with LAG3 blockade groups.
RESULTS
After MWA, the expression of LAG3 was up-regulated on sub-populations of TILs, and introducing LAG3 blockade to MWA postponed tumor development and extended survival in the MC38 tumor model. Flow cytometry and scRNA-seq revealed that LAG3 blockade in combination with MWA markedly boosted the proliferation and the function of CD8 TILs, leading to altered myeloid cells in the TME.
CONCLUSION
Combination therapy of LAG3 blockade and MWA was a unique therapeutic regimen for some solid tumors, and such combination therapy might reprogram the TME to an anti-tumor manner.
背景
免疫检查点抑制剂（ICIs）与其他治疗策略相结合，在各种恶性肿瘤中显示出令人兴奋的结果，ICIs 现已成为当前癌症治疗的金标准。在几项临床前和临床研究中，消融联合免疫治疗已被证明非常有效。我们之前的研究表明，消融联合 ICI 是结直肠癌肝转移（CRLM）的一种潜在的抗癌方案。此外，我们已经报告说，在微波消融（MWA）之后，肿瘤微环境（TME）中 LAG3 的表达上调，表明 LAG3 参与调节免疫抑制性免疫反应，MWA 和 LAG3 阻断联合治疗可能是一种有前途的抗癌治疗策略。
方法
本研究利用经 MWA 治疗的临床前小鼠模型研究了 LAG3 的表达。此外，我们监测了小鼠的肿瘤发展和生存情况，以评估 MWA 单独或联合 LAG3 阻断的抗癌作用。流式细胞术还用于表型分析肿瘤浸润淋巴细胞（TIL）和 CD8 T 细胞效应分子。最后，我们分析了来自 MWA 单独和 MWA 联合 LAG3 阻断组肿瘤中浸润性 CD45 免疫细胞的单细胞 RNA 测序（scRNA-seq）数据。
结果
MWA 后，TIL 的亚群中 LAG3 的表达上调，在 MC38 肿瘤模型中引入 LAG3 阻断可延迟肿瘤发展并延长生存。流式细胞术和 scRNA-seq 显示，LAG3 阻断联合 MWA 可显著促进 CD8 TIL 的增殖和功能，导致 TME 中的髓样细胞发生改变。
结论
LAG3 阻断联合 MWA 的联合治疗是某些实体瘤的独特治疗方案，这种联合治疗可能将 TME 重新编程为抗肿瘤方式。
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