Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy
Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy
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DOI：
10.1158/1078-0432.ccr-16-1433
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发表时间：
2017-02-01
影响因子：
11.5
通讯作者：
Nelson, Brad H.
中科院分区：
文献类型：
--
作者：
Lo, Charlotte S.;Sanii, Sanaz;Nelson, Brad H.
目的：某些形式的化疗可通过免疫原性细胞死亡增强抗肿瘤免疫，导致t细胞活化和肿瘤浸润增加。这种效应可能潜在地使肿瘤对免疫疗法敏感，包括检查点阻断。我们研究了以铂和紫杉烷为基础的卵巢癌化疗是否会引起与这种可能性一致的免疫变化。实验设计：对26例高级别浆液性癌（HGSC）患者新辅助化疗前后匹配的肿瘤样本进行免疫组织化学（IHC）分析，以获得大量免疫细胞和相关因子。在一个扩大的队列（n = 90）中评估化疗后TIL模式的预后意义。结果：新辅助化疗与CD3（+）、CD8（+）、CD8(+) TIA-1（+）、PD-1（+）、CD20(+) TIL密度增高相关。其他免疫亚群和因子没有变化，包括CD79a(+) CD138（+）浆细胞、CD68（+）巨噬细胞和肿瘤细胞上的MHC I类。免疫抑制细胞类型也没有变化，包括FoxP3(+) PD-1（+）细胞（假定的调节性T细胞）、IDO-1（+）细胞和PD-L1（+）细胞（巨噬细胞和肿瘤细胞）。分层聚类揭示了三种反应模式：(i) till高肿瘤在化疗后多种免疫标记物增加；（ii） TILlow肿瘤也有类似的增加，达到与第一组没有区别的模式；（iii） till阴性病例一般仍呈阴性。尽管前两种模式的TIL显著增加，但化疗后TIL的预后意义有限。结论：化疗增强了预先存在的TIL反应，但不能缓解主要的免疫抑制机制或赋予显著的预后益处。我们的发现为针对肿瘤微环境的基线特征进行多管齐下的免疫治疗提供了理论依据。AACR (C) 2016人。
Purpose: Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum-and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.Experimental Design: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n = 90).Results: Neoadjuvant chemotherapy was associated with increased densities of CD3(+), CD8(+), CD8(+) TIA-1(+), PD-1(+) and CD20(+) TIL. Other immune subsets and factors were unchanged, including CD79a(+) CD138(+) plasma cells, CD68(+) macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3(+) PD-1(+) cells (putative regulatory T cells), IDO-1(+) cells, and PD-L1(+) cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TILhigh tumors showed increases in multiple immune markers after chemotherapy; (ii) TILlow tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TILnegative cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. (C)2016 AACR.