Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.
Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.
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对人类非小细胞肺癌病变的单细胞分析改进了肿瘤分类和患者分层。
DOI：
10.1016/j.ccell.2021.10.009
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发表时间：
2021-12-13
期刊：
影响因子：
50.3
通讯作者：
Merad M
中科院分区：
文献类型：
--
作者：
Leader AM;Grout JA;Maier BB;Nabet BY;Park MD;Tabachnikova A;Chang C;Walker L;Lansky A;Le Berichel J;Troncoso L;Malissen N;Davila M;Martin JC;Magri G;Tuballes K;Zhao Z;Petralia F;Samstein R;D'Amore NR;Thurston G;Kamphorst AO;Wolf A;Flores R;Wang P;Müller S;Mellman I;Beasley MB;Salmon H;Rahman AH;Marron TU;Kenigsberg E;Merad M
免疫治疗是非小细胞肺癌(NSCLC)治疗的支柱。虽然肿瘤突变负荷(TMB)与免疫治疗的反应有关，但对基线免疫反应与肿瘤基因型之间的关系知之甚少。使用单细胞RNA测序，我们分析了35个早期NSCLC病变的361,929个细胞。我们确定了一个由PDCD1+CXCL13+激活的T细胞、免疫球蛋白G+浆细胞和SPP1+巨噬细胞组成的细胞模块，称为肺癌激活模块(LCAMhi)。我们证实了LCAMhi在多个非小细胞肺癌队列中的丰富，并且配对的CITE-SEQ建立了一个抗体小组来识别LCAMhi病变。研究发现，LCAM的存在与总体免疫细胞含量无关，并与TMB、肿瘤睾丸抗原和TP53突变相关。即使在TMB中值以上的患者中，高基线LCAM评分也与NSCLC对免疫治疗的增强反应相关，这表明免疫细胞组成虽然与TMB相关，但可能是免疫治疗反应的非多余生物标志物。Leader等人。提供由scRNA-seq和Cite-seq分析的最大的非小细胞肺癌队列，展示治疗初期免疫反应的共享和可变元素，并确定肿瘤突变负担和TP53突变的独立免疫调节作用，从而建立新抗原、驱动因素突变和免疫状态如何结合来驱动免疫治疗反应的精炼模型。
Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1+CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). We confirmed LCAMhi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAMhi lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy. Leader et al. provide the largest NSCLC cohort analyzed by scRNA-seq and CITE-seq, demonstrating shared and variable elements of the treatment-naive immune response and identifying independent immune-modifying effects of tumor mutational burden and TP53 mutation, resulting in a refined model of how neoantigens, driver mutations, and immune state combine to drive immunotherapeutic response.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
DOI：
10.1126/science.1247651
发表时间：
2014-02-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaitin DA;Kenigsberg E;Keren-Shaul H;Elefant N;Paul F;Zaretsky I;Mildner A;Cohen N;Jung S;Tanay A;Amit I
通讯作者：
Amit I
影响因子：
14.9
作者：
Huang PJ;Chiu LY;Lee CC;Yeh YM;Huang KY;Chiu CH;Tang P
通讯作者：
Tang P
影响因子：
64.5
作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
通讯作者：
Carr, Steven A.