Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.
Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.
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DOI：
10.1158/2326-6066.cir-14-0076
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发表时间：
2014-11
影响因子：
10.1
通讯作者：
Hodge JW
中科院分区：
文献类型：
--
作者：
Farsaci B;Donahue RN;Coplin MA;Grenga I;Lepone LM;Molinolo AA;Hodge JW
本研究调查了抗血管生成酪氨酸激酶抑制剂（TKI）与治疗性疫苗结合对肿瘤微环境的影响，特别是血管变化如何影响肿瘤浸润免疫细胞。我们在2种鼠肿瘤模型中使用TKI（舒尼替尼或索拉非尼）与重组疫苗组合进行研究：结肠癌（MC 38-CEA）和乳腺癌（4 T1）。使用3种内皮细胞标志物：CD 31（成熟）、CD 105（未成熟/增殖）和CD 11b（单核细胞）通过免疫组织化学测量肿瘤血管。我们评估了单独使用抗血管生成TKI、单独使用疫苗或TKI与疫苗联合治疗后肿瘤内的氧合、紧密连接、致密性和压力，沿着肿瘤浸润T淋巴细胞（TIL）、髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）的频率和表型。联合方案降低了肿瘤血管系统、致密性、紧密连接和压力，导致血管正常化和肿瘤氧合增加。这种联合治疗还增加了TIL，包括肿瘤抗原特异性CD 8 T细胞，并提高了MDSC和TAM中活化标志物FAS-L、CXCL-9、CD 31和CD 105的表达，导致肿瘤体积减少和无肿瘤动物数量增加。抗血管生成TKI与疫苗联合诱导的抗肿瘤活性改善可能是肿瘤微环境中淋巴和骨髓细胞活化的结果，这是由于血管正常化、肿瘤细胞密度降低以及随之而来的血管灌注和氧合改善。因此，改变肿瘤结构的疗法可以对癌症免疫疗法的有效性产生巨大影响。
This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy.