Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody.
Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody.
复制标题
DOI：
10.1158/0008-5472.can-13-2564
复制
发表时间：
2014-06-01
期刊：
影响因子：
11.2
通讯作者：
Knutson KL
中科院分区：
文献类型：
--
作者：
Karyampudi L;Lamichhane P;Scheid AD;Kalli KR;Shreeder B;Krempski JW;Behrens MD;Knutson KL
肿瘤微环境中的免疫抑制减弱了疫苗诱导的免疫效应物。PD-1/B7-H1是肿瘤微环境中重要的抑制轴。我们在这项研究中的目标是确定在乳腺癌疫苗接种期间和之后阻断这种抑制轴的效果。我们观察到，使用抗PD-1抗体和多肽疫苗（由源自乳腺癌抗原、neu、豆荚蛋白和β-连环蛋白的免疫原性肽组成）作为治疗乳腺癌荷瘤小鼠的联合治疗方案延长了疫苗诱导的无进展生存期。这种延长的存活与具有记忆前体表型的Tc 1和Tc 2 CD 8 T细胞、CD 27 +IL-7 RhiT-betlo的数量增加以及消退肿瘤中PD-1+树突状细胞（DC）数量减少和肿瘤浸润CD 8 T细胞的抗原反应性增强相关。还观察到阻断肿瘤DC上的PD-1增强了CD 8 T细胞上的IL-7 R表达。总之，我们的结果表明PD-1阻断通过改变肿瘤微环境的CD 8 T细胞和DC组分来增强乳腺癌疫苗的功效。鉴于抗PD-1单药治疗最近取得的成功，我们的结果对于开发用于治疗单独抗PD-1单药治疗可能无效的癌症患者（即PD-L1阴性肿瘤）的联合疗法是令人鼓舞的。
Immunosuppression in the tumor microenvironment blunts vaccine induced immune effectors. PD-1/B7-H1 is an important inhibitory axis in the tumor microenvironment. Our goal in this study was to determine the effect of blocking this inhibitory axis during and following vaccination against breast cancer. We observed that using anti-PD-1 antibody and a multi-peptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain and β-catenin) as a combination therapy regimen for the treatment of breast cancer bearing mice prolonged the vaccine-induced progression-free survival period. This prolonged survival was associated with increase in number of Tc1 and Tc2 CD8 T cells with memory precursor phenotype, CD27+IL-7RhiT-betlo and decrease in number of PD-1+ dendritic cells (DCs) in regressing tumors and enhanced antigen reactivity of tumor-infiltrating CD8 T cells. It was also observed that blockade of PD-1 on tumor DCs enhanced IL-7R expression on CD8 T cells. Taken together, our results suggest that PD-1 blockade enhances breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the tumor microenvironment. Given the recent success of anti-PD-1 monotherapy, our results are encouraging for developing combination therapies for the treatment of cancer patients in which anti-PD-1 monotherapy alone may be ineffective (i.e. PD-L1-negative tumors).