RESUMO
Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis. SIGNIFICANCE: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897.
Assuntos
Neoplasias Pulmonares , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Microambiente Tumoral/imunologia , Linfócitos T/imunologia , Células Mieloides/imunologia , Feminino , Masculino , Evasão da Resposta ImuneRESUMO
Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1ß drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1ß-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.
Assuntos
Imunidade Inata , Pulmão , Humanos , Diferenciação Celular , Células Matadoras Naturais , Células EpiteliaisRESUMO
CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.
Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Antígeno B7-H1/genética , Linfócitos T CD8-Positivos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T CD8-Positivos , Carcinoma de Células Renais/genética , Ensaios Clínicos Fase II como Assunto , Retrovirus Endógenos/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Renais/genética , Nivolumabe/farmacologia , Estudos Prospectivos , Análise de Sequência de RNA , Análise de Célula Única , Evasão Tumoral , Microambiente Tumoral , Sequenciamento do ExomaRESUMO
Recent clinical experience has demonstrated that adoptive regulatory T (Treg) cell therapy is a safe and feasible strategy to suppress immunopathology via induction of host tolerance to allo- and autoantigens. However, clinical trials continue to be compromised due to an inability to manufacture a sufficient Treg cell dose. Multipotent adult progenitor cells (MAPCâ) promote Treg cell differentiation in vitro, suggesting they may be repurposed to enhance ex vivo expansion of Tregs for adoptive cellular therapy. Here, we use a Good Manufacturing Practice (GMP) compatible Treg expansion platform to demonstrate that MAPC cell-co-cultured Tregs (MulTreg) exhibit a log-fold increase in yield across two independent cohorts, reducing time to target dose by an average of 30%. Enhanced expansion is coupled to a distinct Treg cell-intrinsic transcriptional program characterized by elevated expression of replication-related genes (CDK1, PLK1, CDC20), downregulation of progenitor and lymph node-homing molecules (LEF1 CCR7, SELL) and induction of intestinal and inflammatory tissue migratory markers (ITGA4, CXCR1) consistent with expression of a gut homing (CCR7lo ß7hi) phenotype. Importantly, we find that MulTreg are more readily expanded from patients with autoimmune disease compared to matched Treg lines, suggesting clinical utility in gut and/or T helper type1 (Th1)-driven pathology associated with autoimmunity or transplantation. Relative to expanded Tregs, MulTreg retain equivalent and robust purity, FoxP3 Treg-Specific Demethylated Region (TSDR) demethylation, nominal effector cytokine production and potent suppression of Th1-driven antigen specific and polyclonal responses in vitro and xeno Graft vs Host Disease (xGvHD) in vivo. These data support the use of MAPC cell co-culture in adoptive Treg therapy platforms as a means to rescue expansion failure and reduce the time required to manufacture a stable, potently suppressive product.
Assuntos
Autoimunidade , Contagem de Linfócitos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/imunologia , Células-Tronco Adultas/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Biomarcadores , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunofenotipagem , Masculino , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials.
Assuntos
Genômica/tendências , Recidiva Local de Neoplasia/genética , Neoplasias/genética , Rastreamento de Células , Progressão da Doença , HumanosRESUMO
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.
Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/imunologia , Linfócitos T/imunologia , Biomarcadores Tumorais/metabolismo , Antígenos CD8/metabolismo , Quimiocina CXCL13/metabolismo , Cromossomos Humanos Par 9/genética , Estudos de Coortes , Ciclina D1/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Amplificação de Genes , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Análise Multivariada , Mutação/genética , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único/genética , Receptores CCR5/metabolismo , Linfócitos T/efeitos dos fármacos , Carga Tumoral/genéticaRESUMO
Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.
Assuntos
Diabetes Mellitus Tipo 1 , Transplante de Células-Tronco Hematopoéticas , Transplante das Ilhotas Pancreáticas , Alemtuzumab/uso terapêutico , Sobrevivência de Enxerto , Humanos , Fenótipo , Linfócitos TRESUMO
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 (Pmeta = 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.
Assuntos
Melanoma/genética , Melanoma/imunologia , Degradação do RNAm Mediada por Códon sem Sentido/genética , Linfócitos T/imunologia , Evasão Tumoral/genética , Transferência Adotiva , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/genética , Mutação da Fase de Leitura/genética , Humanos , Mutação INDEL/genética , Imunoterapia Adotiva , Linfócitos T/transplante , Sequenciamento do ExomaRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Diferenciação Celular/genética , Humanos , Neoplasias Pulmonares/genética , MutaçãoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Heterogeneidade Genética , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genética , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
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.
Assuntos
Antígenos de Neoplasias/imunologia , Evolução Molecular , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Evasão Tumoral/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares/genética , Linfócitos do Interstício Tumoral/imunologia , Masculino , Prognóstico , Microambiente Tumoral/imunologiaRESUMO
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-1hi) 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.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/urina , Urina , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Neoplasias da Bexiga Urinária/patologiaRESUMO
Lymphodepletion strategies are used in the setting of transplantation (including bone marrow, hematopoietic cell, and solid organ) to create space or to prevent allograft rejection and graft versus host disease. Following lymphodepletion, there is an excess of IL-7 available, and T cells that escape depletion respond to this cytokine undergoing accelerated proliferation. Moreover, this environment promotes the skew of T cells to a Th1 pro-inflammatory phenotype. Existing immunosuppressive regimens fail to control this homeostatic proliferative (HP) response, and thus the development of strategies to successfully control HP while sparing T cell reconstitution (providing a functioning immune system) represents a significant unmet need in patients requiring lymphodepletion. Multipotent adult progenitor cells (MAPC®) have the capacity to control T cell proliferation and Th1 cytokine production. Herein, this study shows that MAPC cells suppressed anti-thymocyte globulin-induced cytokine production but spared T cell reconstitution in a pre-clinical model of lymphodepletion. Importantly, MAPC cells administered intraperitoneally were efficacious in suppressing interferon-γ production and in promoting the expansion of regulatory T cells in the lymph nodes. MAPC cells administered intraperitoneally accumulated in the omentum but were not present in the spleen suggesting a role for soluble factors. MAPC cells suppressed lymphopenia-induced cytokine production in a prostaglandin E2-dependent manner. This study suggests that MAPC cell therapy may be useful as a novel strategy to target lymphopenia-induced pathogenic T cell responses in lymphodepleted patients.
Assuntos
Células-Tronco Adultas/imunologia , Rejeição de Enxerto/prevenção & controle , Imunoterapia/métodos , Células-Tronco Pluripotentes/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Transplante , Células-Tronco Adultas/ultraestrutura , Animais , Proliferação de Células , Células Cultivadas , Dinoprostona/metabolismo , Modelos Animais de Doenças , Homeostase , Humanos , Ativação Linfocitária , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Pluripotentes/transplanteRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Imunidade Celular , Memória Imunológica , Ativação Linfocitária/imunologia , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Homeostase , Humanos , Imunomodulação , Contagem de Linfócitos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
BACKGROUND: The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype. METHODS: We analysed whole-exome sequencing data from 5777 solid tumours, spanning 19 cancer types from The Cancer Genome Atlas. We compared the proportion and number of indels across the cohort, with a subset of results replicated in two independent datasets. We assessed in-silico tumour-specific neoantigen predictions by mutation type with pan-cancer analysis, together with RNAseq profiling in renal clear cell carcinoma cases (n=392), to compare immune gene expression across patient subgroups. Associations between indel burden and treatment response were assessed across four checkpoint inhibitor datasets. FINDINGS: We observed renal cell carcinomas to have the highest proportion (0·12) and number of indel mutations across the pan-cancer cohort (p<2·2â×â10-16), more than double the median proportion of indel mutations in all other cancer types examined. Analysis of tumour-specific neoantigens showed that enrichment of indel mutations for high-affinity binders was three times that of non-synonymous SNV mutations. Furthermore, neoantigens derived from indel mutations were nine times enriched for mutant specific binding, as compared with non-synonymous SNV derived neoantigens. Immune gene expression analysis in the renal clear cell carcinoma cohort showed that the presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which correlated (r=0·78) with T-cell activation as measured by CD8-positive expression. Finally, analysis of checkpoint inhibitor response data revealed frameshift indel count to be significantly associated with checkpoint inhibitor response across three separate melanoma cohorts (p=4·7â×â10-4). INTERPRETATION: Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity. FUNDING: Cancer Research UK, UK National Institute for Health Research (NIHR) at the Royal Marsden Hospital National Health Service Foundation Trust, Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, the UK Medical Research Council, the Rosetrees Trust, Novo Nordisk Foundation, the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council.
Assuntos
Antígenos de Neoplasias/genética , DNA de Neoplasias/análise , Mutação da Fase de Leitura , Mutação INDEL , Neoplasias/genética , Neoplasias/imunologia , Linfócitos T CD8-Positivos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Análise Mutacional de DNA , Bases de Dados Genéticas , Exoma , Genes cdc , Genômica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Ativação Linfocitária/genética , Melanoma/genética , Melanoma/imunologia , Fenótipo , Regulação para CimaRESUMO
Immune checkpoint blockade (ICB) is revolutionizing cancer medicine, yet the molecular basis of resistance remains unclear. In a recent issue of Cell, Benci et al. (2016) demonstrate that sustained interferon signaling is central to the development of PD-L1-dependent and -independent resistance to ICB.
Assuntos
Anticorpos Monoclonais , Receptor de Morte Celular Programada 1/imunologia , Antígeno B7-H1 , Humanos , Imunoterapia , NeoplasiasRESUMO
T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1ß-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients.