A conserved dendritic-cell regulatory program limits antitumour immunity

Maier, Bárbara; Leader, Andrew M.; Chen, Shuo; Tung, Navpreet; Chang, Christie; LeBérichel, Jessica; Chudnovskiy, Aleksey; Maskey, Shrisha; Walker, Laura; Finnigan, John P.; Kirkling, Margaret E.; Reizis, Boris; Ghosh, Sourav; D’Amore, Natalie Roy; Bhardwaj, Nina; Rothlin, Carla V.; Wolf, Andrea; Flores, Raja M.; Marron, Thomas U.; Rahman, Adeeb; Kenigsberg, Ephraim; Brown, Brian D.; Mérad, Miriam

doi:10.1038/s41586-020-2134-y

Cited by 533 publications

(707 citation statements)

References 30 publications

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“…We also observed a marked difference in dendritic cell (DC) subsets. First, conventional type 2 dendritic cells (cDC2), plasmacytoid dendritic cells (pDC) and mature regulatory dendritic cells (mregDCs) (60)(61)(62), which can suppress anti-tumor immunity in certain contexts, were prominent DC subtypes in treatment-naïve samples, but absent from CRT specimens (Figure 2A) (63). In contrast, conventional type 1 dendritic cells (cDC1), which activate cytotoxic lymphocytes critical for anti-tumor immunity, was the only DC subset detected in post-CRT tumors (Figure 2A).…”

Section: Neoadjuvant Treatment Has Implications For Anti-tumor Immunitymentioning

confidence: 99%

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Hwang

Jagadeesh

Guo

et al. 2020

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease. Characterizing PDAC by mRNA profiling remains particularly challenging. Previously identified bulk expression subtypes were influenced by contaminating stroma and have not yet informed clinical management, whereas single cell RNA-seq (scRNA-seq) of fresh tumors under-represented key cell types. Here, we developed a robust single-nucleus RNA-seq (snRNA-seq) technique for frozen archival PDAC specimens and used it to study both untreated tumors and those that received neoadjuvant chemotherapy and radiotherapy (CRT). Gene expression programs learned across untreated malignant cell and fibroblast profiles uncovered a clinically relevant molecular taxonomy with improved prognostic stratification compared to prior classifications. Moreover, in the increasingly-adopted neoadjuvant treatment context, there was a depletion of classical-like phenotypes in malignant cells in favor of basal-like phenotypes associated with TNF-NFkB and interferon signaling as well as the presence of novel acinar and neuroendocrine classical-like states, which may be more resilient to cytotoxic treatment. Spatially-resolved transcriptomics revealed an association between malignant cells expressing these basal-like programs and higher immune infiltration with increased lymphocytic content, whereas those exhibiting classical-like programs were linked to sparser macrophage-predominant microniches, perhaps pointing to susceptibility to distinct therapeutic strategies. Our refined molecular taxonomy and spatial resolution can help advance precision oncology in PDAC through informative stratification in clinical trials and insights into differential therapeutic targeting leveraging the immune system.

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Section: Neoadjuvant Treatment Has Implications For Anti-tumor Immunitymentioning

confidence: 99%

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Hwang

Jagadeesh

Guo

et al. 2020

Preprint

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“…We identified conventional DC1 (cDC1) expressing IRF8, WDFY4, and CLEC9A transcripts ( Figure 2A) as well as CD141 and CD26 surface markers ( Figure 2B), and cDC2 expressing high CD1C and FCER1A transcripts as well as CD1c and CD5 protein. We also detected a DC cluster expressing FSCN1 and CCR7 transcripts and elevated HLADR, CD86, PD-L1, and CD40 surface protein which we described as mature DC enriched in regulatory molecules (mregDC) in great detail elsewhere 18 ; in this study we found mregDC were correlated with tumorantigen uptake and thus help define antigen-charged DC 18 . This phenotype was also consistent with an activated DC phenotype detected in lung and liver tumors by others 6,19 .…”

Section: Resultsmentioning

confidence: 57%

“…Since the activation profile of mregDC is crucial for inducing tumor directed T cell responses 18 , we examined the mregDC distribution in tumors by multiplexed immunohistochemical consecutive staining on a single slide (MICSSS) . We stained for DC-LAMP and PD-L1, as the transcripts of these genes (LAMP3 and CD274, respectively) were highly enriched in the mregDC cluster ( Figure 2D).…”

Section: Resultsmentioning

confidence: 99%

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations

Leader

Grout

Chang

et al. 2020

Preprint

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Immunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

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“…These states reflect mature alveolar-like states PPARG+ (M13) and C1QB+ (M5), as well non-tissue resident states SPP1+ (M10), APOE+ (M18) and SEPP1+ (M9) states, and immune-associated states GBP1+ (M7) and MX1+ (M15) (Reyfman et al, 2019; Zilionis et al, 2019). Additionally, this approach uncovered a rare recently described anti-tumor-associated cross-presenting dendritic cell subset (LAMP3+, BIRC3+, CCR7+), identified in both healthy and interstitial lung disease samples as well (Maier et al, 2020).…”

Section: Pan-cluster Comparison Reveals Conserved Cell Subsets and Mamentioning

confidence: 99%

“…(Blériot et al, 2020;Nutt and Chopin, 2020). To perform these functions, these cell types execute diverse and distinct transcriptional programs in response to local and systemic cues (Jaitin et al, 2019;Maier et al, 2020;Okabe and Medzhitov, 2016;Reyes et al, 2020). This transcriptional diversity has been particularly appreciated in macrophages, where the classically-defined dichotomous spectrum has been progressively expanded in favor of a complex spectrum both in vitro and in vivo (Gautier et al, 2012;Li et al, 2019;Rajab et al, 2019;Sica and Mantovani, 2012;Xue et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease

Peters

Blainey

Bryson

2020

Preprint

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SUMMARYMonocytes, dendritic cells, and macrophages, commonly referred to as mononuclear phagocytes (MNPs), are innate immune cells capable of adopting diverse homeostatic and pathogenic phenotypes. Recent single-cell RNA-sequencing studies across many diseases in the lung have profiled this diversity transcriptionally, defining new cellular states and their association with disease. Despite these massive cellular profiling efforts, many studies have focused on defining myeloid dysfunction in specific diseases without identifying common pan-disease trends in the mononuclear phagocyte compartment within the lung. To address these gaps in our knowledge, we collate, process, and analyze 561,390 cellular transcriptomes from 12 studies of the human lung across multiple human diseases. We develop a computational framework to identify and compare dominant gene markers and gene expression programs and characterize MNP diversity in the lung, proposing a conserved dictionary of gene sets. Utilizing this reference, we efficiently identify disease-associated and rare MNP populations across multiple diseases and cohorts. Furthermore, we demonstrate the utility of this dictionary in characterizing a recently published dataset of bronchoalveolar lavage cells from COVID-19 patients and healthy controls which further reveal novel transcriptional shifts directly relatable to other diseases in the lung. These results underline conserved MNP transcriptional programs in lung disease, provide an immediate reference for characterizing the landscape of lung MNPs and establish a roadmap to dissecting MNP transcriptional complexity across tissues.

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A conserved dendritic-cell regulatory program limits antitumour immunity

Cited by 533 publications

References 30 publications

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load and TP53 mutations

Consensus transcriptional states describe human mononuclear phagocyte diversity in the lung across health and disease

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