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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

ABSTRACT: Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

PROVIDER: PRJNA576125 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10230454_1.fastq.gz	Fastqsanger.gz
	SRR10230454_2.fastq.gz	Fastqsanger.gz
	SRR10230455_1.fastq.gz	Fastqsanger.gz
	SRR10230455_2.fastq.gz	Fastqsanger.gz
	SRR10230456_1.fastq.gz	Fastqsanger.gz

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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq]

Project description:Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq]

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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer [RNA-Seq]

Project description:The natural history of small cell lung cancer (SCLC) includes rapid evolution from exquisite chemosensitivity to insurmountable chemoresistance. The mechanisms underlying treatment-resistance in SCLC remain obscure due to scarcity of tissue samples following relapse. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) and its contribution to treatment resistance. To investigate this, we performed single-cell RNAseq analyses of chemo-sensitive and -resistant CDXs, as well as longitudinal analyses of CDXs and patient CTCs. We found increased ITH, heterogeneous expression of pathways known to be associated with resistance, and transcriptional diversity of either therapeutic targets or EMT genes between cellular subpopulations following treatment-resistance to either chemotherapy or targeted therapies (PARP or CHK inhibitors). Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse, with gene expression patterns similar to a CDX from the same patient. These data suggest that treatment-resistance in SCLC is characterized by the presence of coexisting subpopulations of tumor cells with heterogeneous gene expression leading to activation of multiple, concurrent resistance mechanisms. These findings emphasize the need for drug development efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize the depth and duration of initial responses and counteract the rapid increase in ITH and emergence of broad therapeutic resistance.

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Single-cell analyses reveal increasing intratumoral heterogeneity as an essential component of treatment resistance in small cell lung cancer

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2020-02-12 | GSE138474 | GEO

Intratumoral NK Cell and ILC Landscape

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Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma

Project description:Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4) from the CIAO clinical trial (NCT03144778). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent patient cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction of intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in patient tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PD-L1 immune checkpoint blockade, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of anti-tumor immunity and promotes immunotherapy resistance.

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Intratumoral heterogeneity of prostate cancers

Project description:Copy number analyses of regionally separated intratumoral biopsies of prostate cancers. Intratumoral heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumor and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs) that had not been sought, we analyzed multiple regional biopsies from three PCAs using DNA copy number analyses. DNA copy number showed ITH including regional biases in the presentation of a well-known driver of TMPRSS2-ERG fusion. Our analyses identified a substantial level of genetic ITH in unifocal PCAs at the genomic levels, which should be taken into account for the curation of biomarkers in the clinical setting. Four intratumoral biopsies were obtained per tumor for three prostate cancers. Radical prostatectomy tissue from three patients with prostate cancers were obtained. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity). We selected four different areas for biopsy that were at least 5mm apart and were comprised of the most common Gleason pattern (the most common histologic patterns with minimal histologic differences). Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol.

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