Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations

Lesterhuis, W. Joost; Rinaldi, Catherine; Jones, Anya C.; Rozali, Esdy N.; Dick, Ian M.; Khong, Andrea; Boon, Louis; Robinson, Bruce; Nowak, Anna K.; Bosco, Anthony; Lake, Richard

doi:10.1038/srep12298

Cited by 60 publications

(85 citation statements)

References 48 publications

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“…By applying ROC curve analysis (50), we also demonstrated the predictive value of the TMEscore for checkpoint blockade in four separate cohorts of patients with metastatic urothelial cancer (13) treated with the anti-PD-L1 agent (atezolizumab), metastatic melanoma treated with anti-PD-1 (pembrolizumab), advanced melanoma treated with a MAGE-A3 blocker (45), and a mouse model treated with anti-CTLA-4 immunotherapy (46). Consistent with a previous study about an immune signature score (74), we observed a significantly higher TMEscores in responders than in nonresponders undergoing checkpoint blockade therapy.…”

Section: Discussionmentioning

confidence: 99%

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Zeng

Zhou

et al. 2019

Cancer Immunology Research

727

661

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Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNg. Activation of transforming growth factor b, epithelial-mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33-0.54; P < 0.001]. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46-0.89; P ¼ 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07-0.89; P ¼ 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.

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Section: Discussionmentioning

confidence: 99%

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Zeng

Zhou

et al. 2019

Cancer Immunology Research

727

661

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“…(B and C) Distribution of OE of the resistance program in bulk tumors from a lung cancer mouse model treated with anti-CTLA-4 therapy (Lesterhuis et al, 2015)…”

Section: Figurementioning

confidence: 99%

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Jerby‐Arnon

Shah

Cuoco

et al. 2018

Cell

960

1,033

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SUMMARY Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

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“…Here, we made use of the fact that even in the highly homogeneous setting of inbred mouse strains bearing tumors derived from monoclonal cancer cell lines, there remains a dichotomy in responsiveness to treatment with immune checkpoint blockade (6,(16)(17)(18)(19)(20)(21). Against this highly uniform background, we asked whether we could identify a signature in tumors before treatment that would correlate with response, and whether we could use that information to turn nonresponders into responders.…”

Section: Introductionmentioning

confidence: 99%

Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

et al. 2019

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authors contributed equally 2 One Sentence Summary: A STAT1-driven inflammatory phenotype associated with response to checkpoint blocking antibodies can be therapeutically attained and sensitizes cancers to immunotherapy. Abstract:Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by utilizing the fact that inbred mouse strains bearing monoclonal cancer cell line-derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and non-responsive tumors from mice before ICB, and validated the findings in cancer patient cohorts treated with antibodies targeting the PD-1/PD-L1 pathway. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with upregulation of STAT1 and TLR3 signaling, and down-regulation of IL-10 signaling. In addition, responsive tumors had more infiltrating activated natural killer (NK) cells, which were necessary for response. Pretreatment of different mouse strains with large established tumors, using a combination of the STAT1activating cytokine IFNγ, the TLR3 ligand poly(I:C) and an anti-IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment cellular and molecular tumor microenvironment that predicts response to ICB, which can be therapeutically attained. This data anticipates a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB. Introduction:

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Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations

Cited by 60 publications

References 48 publications

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade

Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

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