STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment.
STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment.
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DOI：
10.1136/jitc-2020-001906
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Chelvanambi M;Fecek RJ;Taylor JL;Storkus WJ
肿瘤中的免疫浸润程度，特别是CD 8 + T细胞，极大地影响患者的病程和对介入免疫治疗的反应。肿瘤浸润淋巴细胞（TIL）的增强是有效治疗的关键要素，并且可以通过施用促进肿瘤血管正常化（VN）和/或诱导肿瘤微环境（TME）内三级淋巴样结构（TLS）的发展的药剂来实现。在肿瘤接种后第10、14和17天，将低剂量干扰素基因刺激物（STING）激动剂ADU S-100（5 μg/小鼠）瘤内递送至建立的皮下B16.F10黑素瘤。在不同的时间点分离处理的和对照的肿瘤，以通过定量PCR（qPCR）评估与VN和TLS形成相关的转录变化，使用流式细胞术和免疫荧光显微术确定分离的组织中的必然的免疫细胞组成变化。对用2.5 μg/mL ADU S-100处理的CD 11 c + BMDC或从肿瘤细胞分离的CD 11 c + DC进行体外测定，并通过qPCR分析相关的转录变化或使用DNA微阵列分析相关的转录变化。对于T细胞库β-CDR 3分析，从分离自脾细胞和酶消化的肿瘤的gDNA对T细胞CDR 3进行测序。我们报告说，TME内STING的激活导致黑色素瘤生长减慢，这与抗血管生成因子（包括Tnfsf 15（Vegi）和Cxcl 10）以及TLR诱导因子（包括Ccl 19、Ccl 21、Lta、Ltb和Light）的产生增加有关。由肿瘤内STING激活产生的治疗反应的特征在于改善的VN、CD 8 + T细胞和CD 11 c + DC的增强的肿瘤浸润以及局部TLS新生，所有这些都依赖于STING的宿主表达。与DC在TLS形成中的中心作用一致，ADU S-100激活的mCD 11 c + DC在体外和体内也表现出TLS促进因子的上调表达，包括光毒素-α（LTA）、白细胞介素（IL）-36、炎性趋化因子和I型干扰素。ADU S-100处理小鼠中的TLS形成与高度寡克隆TIL库的发展相关，该库富含TME特有的扩增T细胞克隆型，并且在外周中未检测到。我们的数据支持的前提是，低剂量STING激动剂的递送促进VN和支持TLS形成的促炎性TME，富集TIL库和肿瘤生长控制。
The degree of immune infiltration in tumors, especially CD8+ T cells, greatly impacts patient disease course and response to interventional immunotherapy. Enhancement of tumor infiltrating lymphocyte (TIL) is a critical element of efficacious therapy and one that may be achieved via administration of agents that promote tumor vascular normalization (VN) and/or induce the development of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). Low-dose stimulator of interferon genes (STING) agonist ADU S-100 (5 µg/mouse) was delivered intratumorally to established subcutaneous B16.F10 melanomas on days 10, 14 and 17 post-tumor inoculation. Treated and control tumors were isolated at various time points to assess transcriptional changes associated with VN and TLS formation via quantitative PCR (qPCR), with corollary immune cell composition changes in isolated tissues determined using flow cytometry and immunofluorescence microscopy. In vitro assays were performed on CD11c+ BMDCs treated with 2.5 µg/mL ADU S-100 or CD11c+ DCs isolated from tumor digests and associated transcriptional changes analyzed via qPCR or profiled using DNA microarrays. For T cell repertoireβ-CDR3 analyses, T cell CDR3 was sequenced from gDNA isolated from splenocytes and enzymatically digested tumors. We report that activation of STING within the TME leads to slowed melanoma growth in association with increased production of antiangiogenic factors including Tnfsf15 (Vegi) and Cxcl10, and TLS-inducing factors including Ccl19, Ccl21, Lta, Ltb and Light. Therapeutic responses resulting from intratumoral STING activation were characterized by improved VN, enhanced tumor infiltration by CD8+ T cells and CD11c+ DCs and local TLS neogenesis, all of which were dependent on host expression of STING. Consistent with a central role for DC in TLS formation, ADU S-100-activated mCD11c+ DCs also exhibited upregulated expression of TLS promoting factors including lymphotoxin-α (LTA), interleukin (IL)-36, inflammatory chemokines and type I interferons in vitro and in vivo. TLS formation in ADU S-100-treated mice was associated with the development of a highly oligoclonal TIL repertoire enriched in expanded T cell clonotypes unique to the TME and not detected in the periphery. Our data support the premise that i.t. delivery of low-dose STING agonist promotes VN and a proinflammatory TME supportive of TLS formation, enrichment in the TIL repertoire and tumor growth control.
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改善癌症免疫治疗的免疫血管串扰
DOI：
10.1038/nri.2017.145
发表时间：
2018-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Huang Y;Kim BYS;Chan CK;Hahn SM;Weissman IL;Jiang W
通讯作者：
Jiang W
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
64.8
作者：
Helmink BA;Reddy SM;Gao J;Zhang S;Basar R;Thakur R;Yizhak K;Sade-Feldman M;Blando J;Han G;Gopalakrishnan V;Xi Y;Zhao H;Amaria RN;Tawbi HA;Cogdill AP;Liu W;LeBleu VS;Kugeratski FG;Patel S;Davies MA;Hwu P;Lee JE;Gershenwald JE;Lucci A;Arora R;Woodman S;Keung EZ;Gaudreau PO;Reuben A;Spencer CN;Burton EM;Haydu LE;Lazar AJ;Zapassodi R;Hudgens CW;Ledesma DA;Ong S;Bailey M;Warren S;Rao D;Krijgsman O;Rozeman EA;Peeper D;Blank CU;Schumacher TN;Butterfield LH;Zelazowska MA;McBride KM;Kalluri R;Allison J;Petitprez F;Fridman WH;Sautès-Fridman C;Hacohen N;Rezvani K;Sharma P;Tetzlaff MT;Wang L;Wargo JA
通讯作者：
Wargo JA
DOI：
10.1084/jem.20100052
发表时间：
2011-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lochner M;Ohnmacht C;Presley L;Bruhns P;Si-Tahar M;Sawa S;Eberl G
通讯作者：
Eberl G
影响因子：
10.1
作者：
Cooper ZA;Juneja VR;Sage PT;Frederick DT;Piris A;Mitra D;Lo JA;Hodi FS;Freeman GJ;Bosenberg MW;McMahon M;Flaherty KT;Fisher DE;Sharpe AH;Wargo JA
通讯作者：
Wargo JA