Cytotoxic CD8+ T cells in cancer and cancer immunotherapy

Raskov, Hans; Orhan, Adile; Christensen, Jan Pravsgaard; Gögenür, Ismail

doi:10.1038/s41416-020-01048-4

Cited by 929 publications

(627 citation statements)

References 103 publications

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“…The negative association that we identified is in line with the fact that inhibition of endothelial cells favour an anti-tumor immune response (Klein, 2018). As expected, signalling of CD8 + T cells to dendritic cells and cancer cells was identified as strong positive biomarker (in 14 and 10 of the 18 cancer types respectively, Figure 4C), in line with the crucial role these cells play in immune response and mediation of immunotherapy effects (Raskov et al, 2021). Among the top 30 biomarkers, we also found B cells as receiver cells in 6 different CC pairs (with NK cells, Neutrophils, CD8 + T cells, CD4 + T cells, B cells as sender cells and monocytes).…”

Section: Biomarkers Of Immune Response Based On Cell-cell Communicationsupporting

confidence: 85%

Predictive systems biomarkers of response to immune checkpoint inhibitors

Lapuente-Santana

Hilbers

et al. 2021

Preprint

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Cancer cells can leverage several cell-intrinsic and -extrinsic mechanisms to escape immune system recognition. The inherent complexity of the tumor microenvironment, with its multicellular and dynamic nature, poses great challenges for the extraction of biomarkers of immune response and immunotherapy efficacy. Here, we use RNA-seq data combined with different sources of prior-knowledge to derive system-based signatures of the tumor microenvironment, quantifying immune-cell composition and intra- and inter-cellular communications. We applied multi-task learning to these signatures to predict different hallmarks of immune responses and derive cancer-type-specific models based on interpretable systems biomarkers. By applying our models to independent RNA-seq data from cancer patients treated with PD-1 inhibitors, we demonstrated that our method to Estimate Systems Immune Response (EaSIeR) accurately predicts therapeutic outcome. We anticipate that EaSIeR will be a valuable tool to provide a holistic description of immune responses in complex and dynamic systems such as tumors using available RNA-seq data.

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Section: Biomarkers Of Immune Response Based On Cell-cell Communicationsupporting

confidence: 85%

Predictive systems biomarkers of response to immune checkpoint inhibitors

Lapuente-Santana

Hilbers

et al. 2021

Preprint

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“…As immunotherapy emerges as an effective therapeutic strategy in cancer, T helper (T H ) cells have received widespread interest owing to their integral role in anti-tumor immune responses as has been demonstrated by diverse pre-clinical and clinical models ( 1 , 2 ). While CD8 + cytotoxic T lymphocyte (CTL) function has been explored extensively in recent years in the context of immunotherapy ( 3 ), research shows the crucial role of CD4 + T H cells and its interaction with dendritic cells (DC) to transmit necessary molecular help that stimulates CTL function ( 4 ). T H 1 and T H 2 subclasses of helper T cells engage in molecular crosstalk with multiple immune signaling pathways and have been investigated for their immunotherapeutic relevance in cancer.…”

Section: Cd4 + T Cells Classificationmentioning

confidence: 99%

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

et al. 2021

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Current success of immunotherapy in cancer has drawn attention to the subsets of TH cells in the tumor which are critical for activation of anti-tumor response either directly by themselves or by stimulating cytotoxic T cell activity. However, presence of immunosuppressive pro-tumorigenic TH subsets in the tumor milieu further contributes to the complexity of regulation of TH cell-mediated immune response. In this review, we present an overview of the multifaceted positive and negative effects of TH cells, with an emphasis on regulation of different TH cell subtypes by various immune cells, and how a delicate balance of contradictory signals can influence overall success of cancer immunotherapy. We focus on the regulatory network that encompasses dendritic cell-induced activation of CD4+ TH1 cells and subsequent priming of CD8+ cytotoxic T cells, along with intersecting anti-inflammatory and pro-tumorigenic TH2 cell activity. We further discuss how other tumor infiltrating immune cells such as immunostimulatory TH9 and Tfh cells, immunosuppressive Treg cells, and the duality of TH17 function contribute to tip the balance of anti- vs pro-tumorigenic TH responses in the tumor. We highlight the developing knowledge of CD4+ TH1 immune response against neoantigens/oncodrivers, impact of current immunotherapy strategies on CD4+ TH1 immunity, and how opposing action of TH cell subtypes can be explored further to amplify immunotherapy success in patients. Understanding the nuances of CD4+ TH cells regulation and the molecular framework undergirding the balancing act between anti- vs pro-tumorigenic TH subtypes is critical for rational designing of immunotherapies that can bypass therapeutic escape to maximize the potential of immunotherapy.

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“…Those cells are at the highest level responsible for the direct killing of tumor cells through the secretion of cell membrane perforating molecules, i.e., cathepsin C, perforin, granzymes. The second mechanism, induced by CD8+ Tcells, which leads to cell apoptosis, is their expression of the Fas ligand, which, after binding to its receptor on the targeted cell, induces caspases and endonucleases leading to DNA impairment [31]. Previously, it was shown that a low number of CD8+ Tcells correlates with enhanced tumor growth and poor prognosis [32,33].…”

Section: Ido1 and Its Role In Cancer Developmentmentioning

confidence: 99%

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

Kwiatkowska

Hermanowicz

Przybyszewska-Podstawka

et al. 2021

Cancers

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Background: The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists' interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism

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Cytotoxic CD8+ T cells in cancer and cancer immunotherapy

Cited by 929 publications

References 103 publications

Predictive systems biomarkers of response to immune checkpoint inhibitors

Predictive systems biomarkers of response to immune checkpoint inhibitors

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

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