Retrospective analysis of the immunogenic effects of intra-arterial locoregional therapies in hepatocellular carcinoma: a rationale for combining selective internal radiation therapy (SIRT) and immunotherapy
Retrospective analysis of the immunogenic effects of intra-arterial locoregional therapies in hepatocellular carcinoma: a rationale for combining selective internal radiation therapy (SIRT) and immunotherapy
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DOI：
10.1186/s12885-020-6613-1
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发表时间：
2020-02-19
期刊：
影响因子：
3.8
通讯作者：
Donckier, Vincent
中科院分区：
文献类型：
--
作者：
Craciun, Ligia;de Wind, Roland;Donckier, Vincent
背景免疫治疗是治疗肝硬变患者肝细胞癌的一种有前途的选择，但目前其疗效不一致且不可预测。诱导免疫原性细胞死亡的局部治疗，如经动脉化疗栓塞术(TACE)或选择性内放射治疗(SIRT)，有可能与免疫治疗协同作用。为了开发结合局部治疗和免疫治疗的新方法，需要更好地了解TACE和SIRT对肝细胞癌中免疫细胞的募集和激活的各自影响。为了解决这个问题，我们比较了TACE或SIRT术前治疗后切除的肝细胞癌的肿瘤内免疫浸润物。方法分析32例接受肝部分切除的肝癌患者(SURG，n=32)、16例TACE后(TACE，n=16)和12例SIRT(术前SIRT)患者的临床资料。比较三组的临床病理因素、肿瘤浸润性淋巴细胞(TILs)、CD8(+)T细胞、CD8(+)T细胞、颗粒酶B(GZB)的表达以及术后总生存期和无进展生存期。结果三组患者的临床病理和手术特点相似。与TACE组和SURG组相比，SIRT组切除的肝癌组织中TIL、CD4(+)、CD8(+)T细胞和GZB的表达均显著增加。TACE组与SURG组免疫渗出情况无明显差异。在SIRT组中，照射剂量影响免疫浸润物的类型。在接受100Gy照射的患者中，肿瘤周围区域的CD3(+)细胞比率明显较高，而在接受100Gy照射的患者中，肿瘤内的CD4(+)细胞比率较高。所有组的术后结果相似。不考虑术前治疗，免疫浸润物的类型和程度不影响术后存活率。结论与TACE或非TACE治疗相比，SIRT显著促进肿瘤内效应型免疫细胞的募集/激活。这些结果表明，SIRT是一种比TACE更适合于联合免疫治疗的肝癌治疗方案。对SIRT产生免疫原性效应的最佳剂量和所使用的免疫疗法的类型的评估需要在前瞻性研究中进一步评估。
Background Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT. Methods Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4(+) and CD8(+) T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups. Results Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4(+) and CD8(+) T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3(+) cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4(+) cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival. Conclusions SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.