Comprehensive T cell repertoire characterization of non-small cell lung cancer

Reuben, A; Chiou, S; Gittelman, RM; Li, J; Wang, F; Quek, K; Wang, C; Kheradmand, F; Chen, R; Chow, C; Lin, H; Bernatchez, C; Jalali, A; Hu, X; Wu, C; Eterovic, AK; Parra, ER; Yusko, E; Emerson, R; Benzeno, S; Vignali, M; Wu, X; Ye, Y; Little, LD; Gumbs, C; Mao, X; Song, Zhihao; Tippen, S; Thornton, RL; Cascone, T; Snyder, A; Wargo, JA; Herbst, R; Swisher, S; Kadara, H; Moran, C; Kalhor, N; Scheet, P; Vaporciyan, AA; Sepesi, B; Gibbons, DL; Robins, H; Hwu, P; Heymach, JV; Sharma, P; Allison, JP; Baladandayuthapani, V; Lee, Joseph; Mm, Davis; Wistuba, II; Futreal, P. Andy; Zhang, J

doi:10.21417/ar2019nc

Cited by 37 publications

(69 citation statements)

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“…Immunosuppression in brain metastases has been reported [ 15 , 52 , 53 ]. However, these findings have been confounded by immune privilege associated with the blood-brain barrier (BBB) [ 37 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, the majority of previous studies have focused on the somatic mutations of primary tumors and metastases. Other molecular changes such as somatic copy number aberrations (SCNAs), epigenetic and gene expression alterations, and tumor microenvironment, particularly immune contexture, can play important roles in the metastatic cascade [ 12 – 15 ]. With the intent to comprehensively depict the difference in the molecular and immune landscapes between primary NSCLC tumors and metastases, we performed multiomics profiling of 8 pairs of NSCLC primary tumors, matched distant metastases, and tumor-adjacent morphologically normal tissues.…”

Section: Introductionmentioning

confidence: 99%

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Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Lee

Reuben

et al. 2020

Genome Biol

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Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Lee

Reuben

et al. 2020

Genome Biol

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“…Molecular ITH can have a profound impact on cancer biology 23,24 , and our previous work demonstrated that methylation ITH is associated with clinical outcome in patients with invasive ADC 15 . To assess the evolution of methylation ITH during the progression of lung precancers, we first calculated the "epiallele shift" 25 , the combinatory difference in epiallele status in all captured loci (>60 reads), for each IPN specimen compared to paired normal lung tissues from the same patients.…”

Section: Later-stage Disease Has Higher Epigenetic Ithmentioning

confidence: 92%

“…Cancer evolution is shaped by interaction between cancer cells and host factors, particularly the host immune response. Given T cells' central role in anti-tumor immune surveillance 24,43 , we depicted the T cell infiltration in AIS, MIA and invasive ADC by deconvoluting RNA sequencing data from an independent dataset recently published 44 .…”

Section: Global Hypomethylation Was Associated With Suppressed T Cellmentioning

confidence: 99%

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

Estécio

Chen

et al. 2020

Preprint

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The evolution of DNA methylation at genome level and methylation intra-tumor heterogeneity (ITH) during early lung carcinogenesis has not been systematically studied. We performed multiregional reduced representation bisulfite sequencing (RRBS) of 62 resected lung nodules from 39 patients including atypical adenomatous hyperplasia (AAH, n=14), adenocarcinoma in situ (AIS, n=15), minimally invasive adenocarcinoma (MIA, n=22), and invasive adenocarcinoma (ADC, n=11). We observed significantly higher level of methylation ITH in later-stage lesions and gradual increase in both hyper- and hypomethylation compared to matched normal lung tissues over the course of neoplastic progression. The phyloepigenetic patterns inferred from methylation aberrations resembled those based on somatic mutations suggesting parallel methylation and genetic evolution during the early lung carcinogenesis. De-convolution of transcriptomic profiles from a previously published cohort and RBBS data from the current cohort demonstrated higher ratios of T regulatory cells (Tregs) versus CD8+ T cells in later-stage diseases implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation was associated with higher mutation burden, higher copy number aberration burden, higher allelic imbalance burden as well as higher Treg/CD8 ratio highlighting the potential impact of methylation states on chromosomal instability, mutagenesis and the tumor immune microenvironment.

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“…Immune repertoires represent a vast and diverse collection of B and T cell receptors (BCR and TCR, respectively) and can be used to quantify both past and ongoing immune responses of an individual. The majority of studies in the past have focused primarily on delineating repertoire metrics based on a single variable region: the variable heavy (VH) chain in case of BCRs 32,33 or the variable beta (Vb) chain in case of TCRs [33][34][35] . However, new single-cell sequencing technologies are now enabling a more comprehensive characterization of immune repertoires by capturing both BCR variable light (VL) and VH regions and TCR variable alpha (Va) and Vb chains 36,37 .…”

Section: Introductionmentioning

confidence: 99%

Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

Yermanos

Neumeier

Sandu

et al. 2020

Preprint

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One Sentence SummaryClonally expanded and transcriptionally distinct B and T cells are discovered in brains of elderly mice by single-cell immune repertoire and transcriptome sequencing. AbstractNeuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer's disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system (CNS). Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor (BCR) and T cell receptor (TCR) repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system (CNS) of aged mice. Furthermore, many of these B cells were of the IgM and IgD isotype and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.

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Comprehensive T cell repertoire characterization of non-small cell lung cancer

Cited by 37 publications

References 0 publications

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

Single-cell immune repertoire and transcriptome sequencing reveals that clonally expanded and transcriptionally distinct lymphocytes populate the aged central nervous system in mice

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