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Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

ABSTRACT: 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 (LCAM^hi). We confirmed LCAM^hi enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM^hi 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.

SUBMITTER: Leader AM

PROVIDER: S-EPMC8728963 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

Leader Andrew M AM Grout John A JA Maier Barbara B BB Nabet Barzin Y BY Park Matthew D MD Tabachnikova Alexandra A Chang Christie C Walker Laura L Lansky Alona A Le Berichel Jessica J Troncoso Leanna L Malissen Nausicaa N Davila Melanie M Martin Jerome C JC Magri Giuliana G Tuballes Kevin K Zhao Zhen Z Petralia Francesca F Samstein Robert R D'Amore Natalie Roy NR Thurston Gavin G Kamphorst Alice O AO Wolf Andrea A Flores Raja R Wang Pei P Müller Sören S Mellman Ira I Beasley Mary Beth MB Salmon Hélène H Rahman Adeeb H AH Marron Thomas U TU Kenigsberg Ephraim E Merad Miriam M

Cancer cell 20211111 12

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+ ...[more]

PMID: 34767762

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Project description:ObjectivePatient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.MethodsA total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.ResultsA large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics.ConclusionsOur established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

Dataset Information

Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

Publications

Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification.

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