Recombinant Listeria promotes tumor rejection by CD8(+) T cell-dependent remodeling of the tumor microenvironment.
Recombinant Listeria promotes tumor rejection by CD8(+) T cell-dependent remodeling of the tumor microenvironment.
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DOI：
10.1073/pnas.1801910115
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发表时间：
2018-08-07
影响因子：
11.1
通讯作者：
Dubensky TW Jr
中科院分区：
文献类型：
--
作者：
Deng W;Lira V;Hudson TE;Lemmens EE;Hanson WG;Flores R;Barajas G;Katibah GE;Desbien AL;Lauer P;Leong ML;Portnoy DA;Dubensky TW Jr
几十年来，人们一直致力于利用重组微生物开发治疗性癌症疫苗。然而，治疗性癌症疫苗的潜在机制仍不清楚。在这里，我们比较了基于李斯特氏菌的重组癌症疫苗和合成的长肽和腺病毒递送系统的肿瘤抗原，并描述了基于李斯特氏菌的癌症疫苗抗肿瘤效果的免疫学相关性。我们的结果表明，深刻的抗肿瘤效果需要肿瘤微环境(TME)的重建，这依赖于表达同源肿瘤抗原的减毒双缺失单核细胞增生性李斯特菌诱导的肿瘤特异性CD8+T细胞。总之，这项工作强调了肿瘤疫苗表达同源肿瘤抗原的重要性，并明确了诱导的肿瘤抗原特异性免疫与TME的关系。重塑肿瘤微环境(TME)、肿瘤特异性T细胞的主要功能和阻断抑制信号通路的药物是有效免疫治疗的重要组成部分。我们正在评估表达肿瘤抗原的减毒双缺失单核细胞增生性李斯特菌(LADD-Ag)在临床上的应用。在这里，我们在许多小鼠模型中表明，尽管非重组LADD治疗引起了TME的一些变化，但即使与免疫检查点阻断相结合，也没有观察到抗肿瘤效果。相反，LADD-Ag通过激发肿瘤特异性KLRG1CD1loCD62LCD8CD8+T细胞促进肿瘤排斥反应。这些产生干扰素γ的效应T细胞渗入肿瘤，并将肿瘤从免疫抑制转变为炎症微环境，其特征是调节性T细胞(Treg)水平下降，促炎细胞因子环境，M2巨噬细胞转变为诱导型一氧化氮合酶(INOS)+CD206−M1表型。值得注意的是，这些LaddAg诱导的肿瘤特异性T细胞在原发肿瘤攻击后持续了2个月以上，并迅速控制了继发肿瘤攻击。我们的结果表明，LADD免疫疗法在小鼠身上观察到的显著抗肿瘤效果源于TME重塑，TME重塑是激发强大的、全身肿瘤特异性CD8+T细胞的直接结果。
The development of therapeutic cancer vaccines using recombinant microorganisms has been pursued for many decades. However, the underlying mechanisms of therapeutic cancer vaccines remain unclear. Here we compare recombinant Listeria-based cancer vaccines to synthetic long peptide and adenovirus delivery systems for tumor antigens, and describe immunologic correlates of antitumor efficacy of Listeria-based cancer vaccines. Our results show that the profound antitumor efficacy requires tumor microenvironment (TME) remodeling that depends on tumor-specific CD8+ T cells induced by live-attenuated double-deleted Listeria monocytogenes expressing cognate tumor antigens. Together, this work highlights the importance of cognate tumor antigen expression by cancer vaccines and pinpoints the relationship between induced tumor antigen-specific immunity and the TME. Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L− CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206− M1 phenotype. Remarkably, these LADD-Ag–induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells.
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影响因子：
3.7
作者：
Carrero JA;Vivanco-Cid H;Unanue ER
通讯作者：
Unanue ER
影响因子：
3.9
作者：
Lee SJ;Yang A;Wu TC;Hung CF
通讯作者：
Hung CF
获得的细胞抗性的免疫学基础。
影响因子：
15.3
作者：
MACKANESS, G B
通讯作者：
MACKANESS, G B
影响因子：
32.4
作者：
Slansky, JE;Rattis, FM;Pardoll, DM
通讯作者：
Pardoll, DM
DOI：
10.1084/jem.176.1.287
发表时间：
1992-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Stein M;Keshav S;Harris N;Gordon S
通讯作者：
Gordon S