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

Leader, Andrew M.; Grout, John A.; Maier, Bárbara; Nabet, Barzin Y.; Park, Matthew D.; Tabachnikova, Alexandra; Chang, Christie; Walker, Laura; Lansky, Alona; Bérichel, Jessica Le; Troncoso, Leanna; Malissen, Nausicaa; Davila, Melanie; Martin, Jérôme C.; Magri, Giuliana; Tuballes, Kevin; Zhao, Zhen; Petralia, Francesca; Samstein, Robert M.; D’Amore, Natalie Roy; Thurston, Gavin; Kamphorst, Alice O.; Wolf, Andrea; Flores, Raja M.; Wang, Pei; Müller, Sören; Mellman, Ira; Beasley, Mary Beth; Salmon, Hélène; Rahman, Adeeb; Marron, Thomas U.; Kenigsberg, Ephraim; Mérad, Miriam

doi:10.1016/j.ccell.2021.10.009

Cited by 199 publications

(215 citation statements)

References 65 publications

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“…15c,d). This subset, which we term protumorigenic macrophages and expresses PCOCE2 and SIGLEC1 among top marker genes, closely resembled tissue resident tumor-associated macrophage subsets recently described 36,37 that establish a niche favorable for tumor growth. Three other subsets (clusters M0, M4 and M5) demonsted heterogeneous expression (Extended Data Fig.…”

Section: Mainmentioning

confidence: 57%

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Mehta

Ručević

Sprecher

et al. 2022

Preprint

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Most patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.

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Section: Mainmentioning

confidence: 57%

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Mehta

Ručević

Sprecher

et al. 2022

Preprint

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“…Processed count data was downloaded from gene expression omnibus under GSE121636 (76) GSE123814 (77), GSE139555 (78), GSE145370 (79), GSE154826 (80), GSE155698 (81), GSE176078 (82). Ovarian data was downloaded from code repository (83).…”

Section: Methodsmentioning

confidence: 99%

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Liu

Hogg

Zuo

et al. 2022

Preprint

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Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

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“…In an interesting paper, recently published in Cancer Cell by Leader et al., 5 the authors, deeply studied 361 929 single cells from 35 early-stage NSCLC lesions by using single-cell RNA analyses. The authors integrated the results of single-cell RNA sequencing (scRNA-seq) of immune cells with cellular indexing of transcriptomes and epitopes by sequencing (CITEseq; 3), which allows the evaluation of both scRNA-seq and multiplexed single-cell surface protein measurements.…”

Section: Single-cell Analysis Of Human Non-small-cell Lung Cancer Lesions Refines Tumor Classification and Patient Stratificationmentioning

confidence: 99%

In the literature: December 2021

et al. 2022

View full text Add to dashboard Cite

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

Cited by 199 publications

References 65 publications

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

In the literature: December 2021

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