Dataset Information

Macrophage-Mediated Subversion of Anti-Tumour Immunity.

ABSTRACT: Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8+ T cells following tumour-antigen recognition. However, it is now accepted that even in the case of immunogenic tumours, the effector functions of CD8+ T cells are highly compromised by the presence of an immunosuppressive tumour microenvironment (TME) at the tumour site. Tumour-associated macrophages (TAMs) are among the most abundant non-malignant stromal cell types within the TME and they are crucial drivers of tumour progression, metastasis and resistance to therapy. TAMs are able to regulate either directly or indirectly various aspects of tumour immunity, including T cell recruitment and functions. In this review we discuss the mechanisms by which TAMs subvert CD8+ T cell immune surveillance and how their targeting in combination with ICBs represents a very powerful therapeutic strategy.

SUBMITTER: Quaranta V

PROVIDER: S-EPMC6678757 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Macrophage-Mediated Subversion of Anti-Tumour Immunity.

Quaranta Valeria V Schmid Michael C MC

Cells 20190719 7

Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8<sup>+</sup> T cells following tumour-antigen recognition. However, it is now accepted that even in the case of immunogenic tumours, the effector functions of CD8<sup>+</sup> T cells are highly compromised by the presence of an immunosuppressive tumour microenvironment (TME) ...[more]

PMID: 31331034

Similar Datasets

Project description:BackgroundWhile mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of active immune response could improve the prognosis prediction and provide guidance for current immunotherapy.MethodsThe transcriptomic and whole exome sequence data in The Cancer Genome Atlas were used to examine the relationship between TMB and exhausted CD8+ T cells (Tex), as an indicator of tumour antigen-specific T cells across nine major cancer types. Computational clustering analysis was performed on 4510 tumours to identify different immune profiles. NanoString gene expression analysis and single cell RNA-seq analysis using fresh human breast cancer were performed for finding validation.FindingsTMB was found to be poorly correlated with active immune response in various cancer types. Patient clustering analysis revealed a group of tumours with abundant Tex but low TMB. In those tumours, we observed significantly higher expression of the stimulator of interferon genes (STING) signalling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumours. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation.InterpretationThese results highlight that TMB alone does not fully predict tumour immune profiles, with STING signalling compensating for low TMB in non-hypermutated tumours to enhance anti-tumour immunity. Translating these results, STING agonists may benefit patients with non-hypermutated tumours. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unravelled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy.FundingCity of Hope Christopher Family Endowed Innovation Fund for Alzheimer's Disease and Breast Cancer Research in honor of Vineta Christopher; Breast Cancer Alliance Early Career Investigator Award; National Cancer Institute of the National Institutes of Health under award number R01CA256989 and R01CA240392.

Dataset Information

Macrophage-Mediated Subversion of Anti-Tumour Immunity.

Publications

Macrophage-Mediated Subversion of Anti-Tumour Immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets