Dendritic cells in cancer immunology and immunotherapy

Wculek, Stefanie K.; Cueto, Francisco J.; Mujal, Adriana M.; Melero, Ignacio; Krummel, Matthew F.; Sancho, David

doi:10.1038/s41577-019-0210-z

Cited by 1,821 publications

(1,590 citation statements)

References 163 publications

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“…For example the histone demethylase encoded by KDM6A, where gene deletion has long been associated with the Kabuki immunodeficiency syndrome (Ng et al 2010), is also known to be associated with immune relevant processes including the type I interferon (Li et al 2017) and hypoxia response (Chakraborty et al 2019). In metastatic melanoma we observed ITGAX (alias CD11c), a marker expressed on myeloid cells with well-known impact on classical and monocytic dendritic cell function (Wculek et al 2019), is more frequently mutated in non-T cell-inflamed tumors.…”

Section: Discussionmentioning

confidence: 75%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational profile may also dictate response with some oncogenes (i.e. WNT/β-catenin) known to mediate immuno-suppression. Building on these observations we performed a multi-omic analysis of human cancer correlating the T cell-inflamed gene expression signature with the somatic mutanome and transcriptome for different immune phenotypes, by tumor type and across cancers. Strong correlations were noted between mutations in oncogenes and non-T cellinflamed tumors with examples including IDH1 and GNAQ as well as less well-known genes including KDM6A, CD11c and genes with unknown functions. Conversely, we observe many genes associating with the T cell-inflamed phenotype including VHL and PBRM1, among others.Analyzing gene expression patterns, we identify oncogenic mediators of immune exclusion broadly active across cancer types including HIF1A and MYC. Novel examples from specific tumors include sonic hedgehog signaling in ovarian cancer or hormone signaling and novel transcription factors across multiple tumors. Using network analysis, somatic and transcriptomic events were integrated, demonstrating that most non-T cell-inflamed tumors are influenced by multiple pathways. Validating these analyses, we observe significant inverse relationships between protein levels and the T cell-inflamed gene signature with examples including NRF2 in lung, ERBB2 in urothelial and choriogonadotropin in cervical cancer. Finally, we integrate available databases for drugs that might overcome or augment the identified mechanisms.These results nominate molecular targets and drugs potentially available for immediate translation into clinical trials for patients with cancer.

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Section: Discussionmentioning

confidence: 75%

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Bao

Luke

2019

Preprint

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“…Other cellular therapies based vaccines are focused on DCs. These cells are to date the bona fide antigen presenting cells that activate CD8 + T cell through cross presentation, a process which requires the uptake, processing and exposing the tumour antigens in their MHC‐I to directly eliminate malignant cells (Tran, Robbins, & Rosenberg, ; Wculek et al, ). The potential of DC‐based cancer vaccines is being tested by more than 40 DC‐based cancer vaccines currently in clinical/preclinical stages of development (https://clinicaltrials.gov/).…”

Section: Next Generation Of Immunotherapiesmentioning

confidence: 99%

“…Other cancer immunotherapies include cellular treatments using modified CD8 + T cells targeting tumour cells (CAR-T), tumour infiltrating lymphocytes (TILs) (Chen & Mellman, 2013) or dendritic cell (DC)based vaccines (Wculek et al, 2019).…”

Section: Next Generation Of Immunotherapiesmentioning

confidence: 99%

From cellular microbiology to bacteria‐based next generations of cancer immunotherapies

Osuna-Pérez

Garcia-Ferreras

Veiga

2020

Cellular Microbiology

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Pioneer work by Prof. Cossart among others, studying the interactions between pathogenic bacteria and host cells (this discipline was termed Cellular Microbiology), was fundamental to determine the bacterial infection processes and to improve our knowledge of different cellular mechanisms. The study of bacteria–host interactions also involves in vivo host immune responses, which can be manipulated by bacteria, being these last potent tools for different immunotherapies. During the last years, tumour immunotherapies, mainly the use of antibodies that target immune checkpoints [checkpoint inhibitors (CPI)], have been a revolution in oncology, allowing the treatment of tumours otherwise with very bad prognosis. In the same direction, bacteria inoculations have been used from long to treat some cancers; for example, non‐muscle‐invasive bladder cancer can be successfully treated with the bacterium Bacillus Calmette Guerin (BCG). More recently, it has been shown that microbiota could determine the success of CPI immunotherapies and intense research is being performed in order to use bacteria as immunotherapy tools due to their ability to activate the immune system. In this context, to expand the knowledge of the bacteria–immune system interactions will be fundamental to improve tumour immunotherapies.

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“…Type 1 conventional DCs (cDC1) are critical in mounting cytotoxic CD8 + T lymphocyte (CTL) immune responses against extracellular pathogens (Merad et al, 2013) and cancers (Cancel et al, 2019;Wculek et al, 2020), in part due to their high efficacy at cross-presenting exogenous antigens to CD8 + T cells. Through their capacity to rapidly produce large amount of bioactive IL-12 Reis e Sousa et al, 1997), cDC1 are also good activators of innate lymphoid cells (ILCs), such as Natural Killer (NK) cells, and of T cell subsets with innate-like functions such as memory CD8 + T cells (Mashayekhi et al, 2011;Miyake et al, 2009;Alexandre et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

NK cells orchestrate splenic cDC1 migration to potentiate antiviral protective CD8+ T cell responses

Ghilas¹,

Ambrosini²,

Cancel³

et al. 2020

Preprint

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2 Summary (150 words max):A successful immune response relies on a tightly regulated delivery of the right signals to the right cells at the right time. Here we show that innate and innate-like lymphocytes use two mechanisms to orchestrate in time and space the functions of conventional type 1 dendritic cells (cDC1) in spleen. Early after murine cytomegalovirus infection, XCL1 production by lymphocytes with innate functions attracts red pulp cDC1 near IFN--producing NK cells, generating superclusters around infected cells in the marginal zone. There, cDC1 and NK cells physically interact reinforcing their reciprocal activation. Targeted IL-12 delivery and IL-15/IL-15R transpresentation by cDC1 trigger NK cell activation and expansion. In return, activated NK cells deliver GM-CSF to cDC1, triggering their CCR7-dependent relocalization into the T cell zone. This NK cell-dependent licensing of cDC1 accelerates the priming of virusspecific CD8 + T cells. Our findings reveal a novel mechanism through which cDC1 bridge innate and adaptive immunity.

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Dendritic cells in cancer immunology and immunotherapy

Cited by 1,821 publications

References 163 publications

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

From cellular microbiology to bacteria‐based next generations of cancer immunotherapies

NK cells orchestrate splenic cDC1 migration to potentiate antiviral protective CD8+ T cell responses

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