Lung Cancer Subtypes Generate Unique Immune Responses.
Lung Cancer Subtypes Generate Unique Immune Responses.
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DOI：
10.4049/jimmunol.1600576
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Houghton AM
中科院分区：
文献类型：
--
作者：
Busch SE;Hanke ML;Kargl J;Metz HE;MacPherson D;Houghton AM
肺癌是全球癌症相关死亡的主要原因，是一种由多种组织学亚型组成的异质性疾病，具有不同的突变特征。基于免疫的疗法在肺癌患者的治疗中显示出初步的前景，但目前受到总体应答率较低的限制。我们试图确定宿主对肺癌的免疫反应是否至少部分地由组织学和遗传差异来预测，因为这种相关性将具有重要的临床后果。利用小鼠肺癌模型，我们发现小细胞肺癌(SCLC)和肺腺癌(ADCA)表现出肿瘤微环境中独特的免疫细胞成分。与肺ADCA相比，SCLC的白细胞总数显著减少，这在人肺癌标本中得到了证实。我们使用Kras、TP53和EGFR突变驱动的三种肺ADCA模型，进一步确定了免疫细胞含量的关键差异。尽管EGFR突变的癌症表现出强大的髓系细胞募集，但它们未能启动CD8+免疫反应。相比之下，Kras突变肿瘤显示出多种免疫细胞类型的显著扩张，包括CD8+细胞、调节性T细胞、产生IL17A的淋巴细胞和髓系细胞。一个注明KRAS和EGFR突变的人类组织微阵列证实了人类肺腺癌CD8+含量降低的发现。综上所述，这些发现为肺ADCA和SCLC的免疫细胞环境奠定了坚实的基础知识，并表明分子和组织学特征塑造了宿主对癌症的免疫反应。
Lung cancer – the leading cause of cancer-related deaths worldwide – is a heterogeneous disease comprised of multiple histologic subtypes that harbor disparate mutational profiles. Immune-based therapies have shown initial promise in the treatment of lung cancer patients but are currently limited by low overall response rates. We sought to determine whether the host immune response to lung cancer is predicated, at least in part, by histologic and genetic differences, as such correlations would have important clinical ramifications. Using mouse models of lung cancer, we show that small cell lung cancer (SCLC) and lung adenocarcinoma (ADCA) exhibit unique immune cell composition of the tumor microenvironment. The total amount of leukocyte content was markedly reduced in SCLC compared to lung ADCA, which was validated in human lung cancer specimens. We further identified key differences in immune cell content using three models of lung ADCA driven by mutations in Kras, Tp53, and Egfr. Although Egfr-mutant cancers displayed robust myeloid cell recruitment, they failed to mount a CD8+ immune response. In contrast, Kras-mutant tumors displayed significant expansion of multiple immune cell types, including CD8+ cells, regulatory T cells, IL17A-producing lymphocytes, and myeloid cells. A human tissue microarray annotated for KRAS and EGFR mutations validated the finding of reduced CD8+ content in human lung adenocarcinoma. Taken together, these findings establish a strong foundational knowledge of the immune cell contexture of lung ADCA and SCLC and suggest that molecular and histological traits shape the host immune response to cancer.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
肿瘤浸润的调节性T细胞抑制内源性细胞毒性T细胞对肺腺癌的反应。
DOI：
10.4049/jimmunol.1301317
发表时间：
2013-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ganesan AP;Johansson M;Ruffell B;Yagui-Beltrán A;Lau J;Jablons DM;Coussens LM
通讯作者：
Coussens LM
影响因子：
64.5
作者：
Govindan R;Ding L;Griffith M;Subramanian J;Dees ND;Kanchi KL;Maher CA;Fulton R;Fulton L;Wallis J;Chen K;Walker J;McDonald S;Bose R;Ornitz D;Xiong D;You M;Dooling DJ;Watson M;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
10.5
作者：
Guo, Jessie Yanxiang;Karsli-Uzunbas, Gizem;White, Eileen
通讯作者：
White, Eileen