Publications by authors named "Sergio A Quezada"

82 Publications

CD25-T-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity.

Nat Cancer 2020 Dec 9;1(12):1153-1166. Epub 2020 Nov 9.

Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK.

Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.
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http://dx.doi.org/10.1038/s43018-020-00133-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116816PMC
December 2020

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.

Cell 2021 Feb 27;184(3):596-614.e14. Epub 2021 Jan 27.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK. Electronic address:

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.
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http://dx.doi.org/10.1016/j.cell.2021.01.002DOI Listing
February 2021

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma.

Nat Commun 2021 01 19;12(1):444. Epub 2021 Jan 19.

Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland.

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4 T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
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http://dx.doi.org/10.1038/s41467-020-20599-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815781PMC
January 2021

The Great Debate at 'Immunotherapy Bridge', Naples, December 5, 2019.

J Immunother Cancer 2020 08;8(2)

Early Phase Clinical Trials Program, Developmental Therapeutics Program, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.
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http://dx.doi.org/10.1136/jitc-2020-000921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449295PMC
August 2020

The T cell differentiation landscape is shaped by tumour mutations in lung cancer.

Nat Cancer 2020 May 22;1(5):546-561. Epub 2020 May 22.

Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, WC1E 6BT, United Kingdom.

Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets, with significant phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.
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http://dx.doi.org/10.1038/s43018-020-0066-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115931PMC
May 2020

Escape from nonsense-mediated decay associates with anti-tumor immunogenicity.

Nat Commun 2020 07 30;11(1):3800. Epub 2020 Jul 30.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.

Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed fs-indels are enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (P = 0.0039). NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting. Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit. Analysis of functional T cell reactivity screens from personalized vaccine studies shows direct evidence of fs-indel derived neoantigens eliciting immune response, particularly those with highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design.
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http://dx.doi.org/10.1038/s41467-020-17526-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393139PMC
July 2020

Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer.

Cancer Discov 2020 Oct 20;10(10):1489-1499. Epub 2020 Jul 20.

Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom.

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, signaling is upregulated, and the immunomodulator is downregulated. Changes appear intrinsic to the carcinoma lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1366DOI Listing
October 2020

Geospatial immune variability illuminates differential evolution of lung adenocarcinoma.

Nat Med 2020 07 27;26(7):1054-1062. Epub 2020 May 27.

Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.
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http://dx.doi.org/10.1038/s41591-020-0900-xDOI Listing
July 2020

Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4PD-1 Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma.

Clin Cancer Res 2020 07 27;26(13):3443-3454. Epub 2020 Mar 27.

Research Department of Haematology, University College London Cancer Institute, London, United Kingdom.

Purpose: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.

Experimental Design: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.

Results: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4):Treg ratio and increased frequency of PD-1-expressing CD4 cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4PD-1 cells displayed transcriptional and secretory features of dysfunction.

Conclusions: BM-infiltrating T-cell subsets, specifically Tregs and PD-1-expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1714DOI Listing
July 2020

Regulatory T Cells Restrain Interleukin-2- and Blimp-1-Dependent Acquisition of Cytotoxic Function by CD4 T Cells.

Immunity 2020 01 7;52(1):151-166.e6. Epub 2020 Jan 7.

Cancer Immunology Unit, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Research Department of Haematology, University College London, Cancer Institute, London WC1E 6DD, UK. Electronic address:

In addition to helper and regulatory potential, CD4 T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4 T cells following immunotherapy. CD4 transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4 T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4 T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.
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http://dx.doi.org/10.1016/j.immuni.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369640PMC
January 2020

Tumour Dormancy and Reawakening: Opportunities and Challenges.

Trends Cancer 2019 12 25;5(12):762-765. Epub 2019 Nov 25.

Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.

Tumour dormancy presents challenges for clinical control and opportunities for scientific discovery. Current pictures of the mechanisms of tumour dormancy and reawakening remain incomplete. The Cancer Research UK's third Marshall Symposium explored tumour dormancy and reawakening in all their forms. In this forum article, we highlight the key challenges and opportunities discussed at this symposium.
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http://dx.doi.org/10.1016/j.trecan.2019.10.010DOI Listing
December 2019

Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer.

Nat Med 2019 10 7;25(10):1549-1559. Epub 2019 Oct 7.

Division of Infection and Immunity, University College London, London, UK.

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8 tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
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http://dx.doi.org/10.1038/s41591-019-0592-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890490PMC
October 2019

Tissue-resident memory CD8 T cells amplify anti-tumor immunity by triggering antigen spreading through dendritic cells.

Nat Commun 2019 09 27;10(1):4401. Epub 2019 Sep 27.

Laboratory of Immunoncology, Fundación Ciencia & Vida, Santiago, Chile.

Tissue-resident memory CD8 T (Trm) cells mediate potent local innate and adaptive immune responses and play a central role against solid tumors. However, whether Trm cells cross-talk with dendritic cells (DCs) to support anti-tumor immunity remains unclear. Here we show that antigen-specific activation of skin Trm cells leads to maturation and migration to draining lymph nodes of cross-presenting dermal DCs. Tumor rejection mediated by Trm cells triggers the spread of cytotoxic CD8 T cell responses against tumor-derived neo- and self-antigens via dermal DCs. These responses suppress the growth of intradermal tumors and disseminated melanoma lacking the Trm cell-targeted epitope. Moreover, analysis of RNA sequencing data from human melanoma tumors reveals that enrichment of a Trm cell gene signature associates with DC activation and improved survival. This work unveils the ability of Trm cells to amplify the breath of cytotoxic CD8 T cell responses through DCs, thereby strengthening anti-tumor immunity.
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http://dx.doi.org/10.1038/s41467-019-12319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765014PMC
September 2019

Regulatory T cells in cancer: where are we now?

Immunology 2019 07;157(3):187-189

Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK.

There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to our understanding of the fundamental biology of tumour immunosuppression but also to the design of new immunotherapeutic approaches. The substantially shared biology of CD4 conventional T (Tconv) and Treg cells necessitates a detailed understanding of the potentially opposing functional consequences that immunotherapies will have on Treg and Tconv cells, a prominent example being the potential for Treg-mediated hyperprogressive disease following anti-PD-1 therapy. Such understanding will aid patient stratification and the rational design of combination therapies. It is also becoming clear, however, that Treg cells within tumours exhibit distinct biological features to both Tconv cells and Treg cells in other tissues. These distinct features provide the opportunity for development of targeted immunotherapies with greater efficacy and reduced potential for inducing systemic toxicity.
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http://dx.doi.org/10.1111/imm.13088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587319PMC
July 2019

Anti-CTLA-4 synergizes with dendritic cell-targeted vaccine to promote IL-3-dependent CD4 effector T cell infiltration into murine pancreatic tumors.

Ann N Y Acad Sci 2019 06 4;1445(1):62-73. Epub 2019 Apr 4.

Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, The Rockefeller University, New York City, New York.

One successful class of cancer immunotherapies, immune checkpoint inhibitory antibodies, disrupts key pathways that regulate immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These agents unleash the potency of antigen-experienced T cells that have already been induced as a consequence of the existing tumor. But only 20% of cancers naturally induce T cells. For most cancers, vaccines are require to induce and mobilize T effector cells (T ) to traffick into tumors. We evaluated the effects of anti-CTLA-4 given in combination with an antigen-specific dendritic cell vaccine on intratumoral T in a murine pancreatic cancer model. The dendritic cell-targeted tumor antigen plus anti-CTLA-4 significantly increased the number of vaccine-induced CD4 T within the tumor. This increase was accompanied by a reduction in the size of the peripheral CD4 T pool. We also found that IL-3 production by activated CD4 T cells was significantly increased with this combination. Importantly, the CD4 T response was attenuated in Il3 mice, suggesting mediation of the effect by IL-3. Finally, the induced T cell infiltration was associated with activation of the tumor endothelium by T cell-derived IL-3. Our findings collectively provide a new insight into the mechanism driving T infiltration and vascular activation in a murine pancreatic cancer model, specifically identifying a new role for IL-3 in the anticancer immune response.
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http://dx.doi.org/10.1111/nyas.14049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557673PMC
June 2019

Neoantigen-directed immune escape in lung cancer evolution.

Nature 2019 03 20;567(7749):479-485. Epub 2019 Mar 20.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK.

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.
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http://dx.doi.org/10.1038/s41586-019-1032-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954100PMC
March 2019

Author Correction: Pan-cancer deconvolution of tumour composition using DNA methylation.

Nat Commun 2018 11 2;9(1):4642. Epub 2018 Nov 2.

School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.

The original version of this Article contained an error in Figure 4. In panel a, the colour code for hot and cold clusters was inadvertently inverted. In the correct version of panel a, the hot clusters are blue and the cold clusters are yellow. This error has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07155-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214991PMC
November 2018

Intratumoral Immunotherapy with XCL1 and sFlt3L Encoded in Recombinant Semliki Forest Virus-Derived Vectors Fosters Dendritic Cell-Mediated T-cell Cross-Priming.

Cancer Res 2018 12 8;78(23):6643-6654. Epub 2018 Oct 8.

Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, and Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.

: Multiple lines of evidence indicate a critical role of antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1, respectively, constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to the tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory mAbs. Therapeutic effects were abolished by CD8β T-cell depletion and were enhanced by CD4 T-cell depletion, but not by T regulatory cell predepletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following the intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T-cell depletion. SIGNIFICANCE: These findings demonstrate that transgenic expression of sFLT3L and XCL1 in tumor cells mediates cross-priming of, and elicits potent antitumor activity from, CD8 T lymphocytes, particularly in combination with CD4 T-cell depletion.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0933DOI Listing
December 2018

Lost in Translation: Deciphering the Mechanism of Action of Anti-human CTLA-4.

Clin Cancer Res 2019 02 5;25(4):1130-1132. Epub 2018 Oct 5.

Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, United Kingdom.

Despite a number of preclinical studies demonstrating that the activity of anti-CTLA-4 antibodies in murine models of cancer relies on effector T-cell activation and regulatory T cell depletion, the activity of the clinical antibodies remains controversial. To decipher such mechanisms is critical to the development of novel and more potent immunotherapies.See related article by Sharma et al., p. 1233.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2509DOI Listing
February 2019

Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

J Exp Med 2018 11 26;215(11):2748-2759. Epub 2018 Sep 26.

Cancer Immunology Unit, University College London (UCL) Cancer Institute, London, England, UK

Despite the advances in cancer immunotherapy, only a fraction of patients with bladder cancer exhibit responses to checkpoint blockade, highlighting a need to better understand drug resistance and identify rational immunotherapy combinations. However, accessibility to the tumor prior and during therapy is a major limitation in understanding the immune tumor microenvironment (TME). Herein, we identified urine-derived lymphocytes (UDLs) as a readily accessible source of T cells in 32 patients with muscle invasive bladder cancer (MIBC). We observed that effector CD8 and CD4 cells and regulatory T cells within the urine accurately map the immune checkpoint landscape and T cell receptor repertoire of the TME. Finally, an increased UDL count, specifically high expression of PD-1 (PD-1) on CD8 at the time of cystectomy, was associated with a shorter recurrence-free survival. UDL analysis represents a dynamic liquid biopsy that is representative of the bladder immune TME that may be used to identify actionable immuno-oncology (IO) targets with potential prognostic value in MIBC.
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http://dx.doi.org/10.1084/jem.20181003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219732PMC
November 2018

Pan-cancer deconvolution of tumour composition using DNA methylation.

Nat Commun 2018 08 13;9(1):3220. Epub 2018 Aug 13.

School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK.

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.
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http://dx.doi.org/10.1038/s41467-018-05570-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089972PMC
August 2018

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation.

Cell Rep 2018 07;24(3):630-641

Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London SE1 1UL, UK; KCL Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK; UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK. Electronic address:

The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and to be released on exosomes. A high-content siRNA screen identified the endosomal sorting complexes required for transport (ESCRT)-associated protein ALIX as a regulator of both EGFR activity and PD-L1 surface presentation in basal-like breast cancer (BLBC) cells. ALIX depletion results in prolonged and enhanced stimulation-induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface. Increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells. An inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immunocompetent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment. Our data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR and may, therefore, present a diagnostic and therapeutic target for BLBC.
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http://dx.doi.org/10.1016/j.celrep.2018.06.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077252PMC
July 2018

The function and dysfunction of memory CD8 T cells in tumor immunity.

Immunol Rev 2018 05;283(1):194-212

Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK.

The generation and maintenance of CD8 T cell memory is crucial to long-term host survival, yet the basic tenets of CD8 T cell immunity are still being established. Recent work has led to the discovery of tissue-resident memory cells and refined our understanding of the transcriptional and epigenetic basis of CD8 T cell differentiation and dysregulation. In parallel, the unprecedented clinical success of immunotherapy has galvanized an intense, global research effort to decipher and de-repress the anti-tumor response. However, the progress of immunotherapy is at a critical juncture, since the efficacy of immuno-oncology agents remains confined to a fraction of patients and often fails to provide durable benefit. Unlocking the potential of immunotherapy requires the design of strategies that both induce a potent effector response and reliably forge stable, functional memory T cell pools capable of protecting from recurrence or relapse. It is therefore essential that basic and emerging concepts of memory T cell biology are rapidly and faithfully transposed to advance therapeutic development in cancer immunotherapy. This review highlights seminal and recent reports in CD8 T cell memory and tumor immunology, and evaluates recent data from solid cancer specimens in the context of the key paradigms from preclinical models. We elucidate the potential significance of circulating effector cells poised downstream of neoantigen recognition and upstream of T cell dysfunction and propose that cells in this immunological 'sweet spot' may be key anti-tumor effectors.
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http://dx.doi.org/10.1111/imr.12657DOI Listing
May 2018

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

Cancer Cell 2018 04 22;33(4):649-663.e4. Epub 2018 Mar 22.

Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address:

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8 to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
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http://dx.doi.org/10.1016/j.ccell.2018.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904288PMC
April 2018

Expansion of airway basal epithelial cells from primary human non-small cell lung cancer tumors.

Int J Cancer 2018 07 6;143(1):160-166. Epub 2018 Apr 6.

Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom.

Pre-clinical non-small cell lung cancer (NSCLC) models are poorly representative of the considerable inter- and intra-tumor heterogeneity of the disease in patients. Primary cell-based in vitro models of NSCLC are therefore desirable for novel therapy development and personalized cancer medicine. Methods have been described to generate rapidly proliferating epithelial cell cultures from multiple human epithelia using 3T3-J2 feeder cell culture in the presence of Y-27632, a RHO-associated protein kinase (ROCK) inhibitor, in what are known as "conditional reprograming conditions" (CRC) or 3T3 + Y. In some cancer studies, variations of this methodology have allowed primary tumor cell expansion across a number of cancer types but other studies have demonstrated the preferential expansion of normal epithelial cells from tumors in such conditions. Here, we report our experience regarding the derivation of primary NSCLC cell cultures from 12 lung adenocarcinoma patients enrolled in the Tracking Cancer Evolution through Therapy (TRACERx) clinical study and discuss these in the context of improving the success rate for in vitro cultivation of cells from NSCLC tumors.
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http://dx.doi.org/10.1002/ijc.31383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969061PMC
July 2018

Chromatin regulation and immune escape.

Science 2018 02;359(6377):745-746

Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, University College London, London, UK.

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http://dx.doi.org/10.1126/science.aat0383DOI Listing
February 2018

Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade.

Sci Transl Med 2018 01;10(422)

Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK.

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
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http://dx.doi.org/10.1126/scitranslmed.aam7577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276984PMC
January 2018

Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

Authors:
Christopher Abbosh Nicolai J Birkbak Gareth A Wilson Mariam Jamal-Hanjani Tudor Constantin Raheleh Salari John Le Quesne David A Moore Selvaraju Veeriah Rachel Rosenthal Teresa Marafioti Eser Kirkizlar Thomas B K Watkins Nicholas McGranahan Sophia Ward Luke Martinson Joan Riley Francesco Fraioli Maise Al Bakir Eva Grönroos Francisco Zambrana Raymondo Endozo Wenya Linda Bi Fiona M Fennessy Nicole Sponer Diana Johnson Joanne Laycock Seema Shafi Justyna Czyzewska-Khan Andrew Rowan Tim Chambers Nik Matthews Samra Turajlic Crispin Hiley Siow Ming Lee Martin D Forster Tanya Ahmad Mary Falzon Elaine Borg David Lawrence Martin Hayward Shyam Kolvekar Nikolaos Panagiotopoulos Sam M Janes Ricky Thakrar Asia Ahmed Fiona Blackhall Yvonne Summers Dina Hafez Ashwini Naik Apratim Ganguly Stephanie Kareht Rajesh Shah Leena Joseph Anne Marie Quinn Phil A Crosbie Babu Naidu Gary Middleton Gerald Langman Simon Trotter Marianne Nicolson Hardy Remmen Keith Kerr Mahendran Chetty Lesley Gomersall Dean A Fennell Apostolos Nakas Sridhar Rathinam Girija Anand Sajid Khan Peter Russell Veni Ezhil Babikir Ismail Melanie Irvin-Sellers Vineet Prakash Jason F Lester Malgorzata Kornaszewska Richard Attanoos Haydn Adams Helen Davies Dahmane Oukrif Ayse U Akarca John A Hartley Helen L Lowe Sara Lock Natasha Iles Harriet Bell Yenting Ngai Greg Elgar Zoltan Szallasi Roland F Schwarz Javier Herrero Aengus Stewart Sergio A Quezada Karl S Peggs Peter Van Loo Caroline Dive C Jimmy Lin Matthew Rabinowitz Hugo J W L Aerts Allan Hackshaw Jacqui A Shaw Bernhard G Zimmermann Charles Swanton

Nature 2018 02 20;554(7691):264. Epub 2017 Dec 20.

This corrects the article DOI: 10.1038/nature22364.
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http://dx.doi.org/10.1038/nature25161DOI Listing
February 2018

Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia.

Lancet 2017 11;390(10110):2343-2345

Department of Medical Oncology, Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital, Imperial College London, London W6 8RF, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(17)32894-5DOI Listing
November 2017