Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment.
Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment.
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DOI：
10.1073/pnas.1720948115
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发表时间：
2018-04-24
影响因子：
11.1
通讯作者：
Donnadieu E
中科院分区：
文献类型：
--
作者：
Peranzoni E;Lemoine J;Vimeux L;Feuillet V;Barrin S;Kantari-Mimoun C;Bercovici N;Guérin M;Biton J;Ouakrim H;Régnier F;Lupo A;Alifano M;Damotte D;Donnadieu E
癌症免疫治疗是一种有前途的治疗干预。然而，只有一小部分癌症患者出现了完全和持久的反应。限制治疗成功的一个关键因素是肿瘤细胞区域缺乏T细胞，这种情况被称为“免疫排斥”。在这里，我们提供的证据表明，肿瘤相关的巨噬细胞（TAM）是一个重要的决定因素，建立一个T细胞排除肿瘤表型。在人类和小鼠肿瘤中，我们发现由于与TAM的长期相互作用，CD 8 T细胞迁移和侵入肿瘤巢的能力很差。TAM的消耗恢复了T细胞迁移和浸润到肿瘤胰岛中，并提高了抗PD-1免疫疗法的功效。这项研究强调了结合靶向TAM和免疫检查点蛋白的方法的基本原理。在大部分癌症患者中，CD 8 T细胞被排除在癌细胞附近。CD 8 T细胞无法到达肿瘤细胞被认为是对癌症免疫疗法产生抗性的重要机制。我们发现，在人肺鳞状细胞癌中，从肿瘤胰岛中排除CD 8 T细胞与临床结局差和淋巴细胞运动性低相关，如通过新鲜肿瘤切片的动态成像所评估。在肿瘤间质中，巨噬细胞通过与CD 8 T细胞形成持久的相互作用来介导淋巴细胞捕获。使用具有明确基质和肿瘤细胞区域的小鼠肿瘤模型，用PLX 3397（集落刺激因子-1受体（CSF-1 R）抑制剂）耗尽巨噬细胞。我们的研究结果表明，CSF-1 R阻断增强CD 8 T细胞迁移和浸润到肿瘤胰岛。虽然这种治疗单独对肿瘤生长的影响较小，但其与抗PD-1治疗的组合进一步增加了与恶性细胞密切接触的CD 8 T细胞的积累，并延迟肿瘤进展。这些数据表明，巨噬细胞介导的T细胞排斥的减少增加了CD 8 T细胞对肿瘤的监视，并使肿瘤对抗PD-1治疗更敏感。
Cancer immunotherapy is a promising therapeutic intervention. However, complete and durable responses are seen in only a fraction of cancer patients. A key factor that limits therapeutic success is the lack of T cells in tumor cell regions, a profile termed “immune-excluded.” Here, we provide evidence that tumor-associated macrophages (TAMs) are an important determinant of the establishment of a T cell-excluded tumor phenotype. In human and murine tumors, we found that CD8 T cells poorly migrate and invade tumor nests due to long-lasting interactions with TAMs. The depletion of TAMs restores T cell migration and infiltration into tumor islets and improves the efficacy of anti–PD-1 immunotherapy. This study highlights the rationale of combining approaches targeting TAM and immune checkpoint proteins. In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti–PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti–PD-1 treatment.
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单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
32.4
作者：
Honda T;Egen JG;Lämmermann T;Kastenmüller W;Torabi-Parizi P;Germain RN
通讯作者：
Germain RN
DOI：
10.1084/jem.20061890
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boissonnas A;Fetler L;Zeelenberg IS;Hugues S;Amigorena S
通讯作者：
Amigorena S
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D