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Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in â¼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-ß-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.
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Mutação em Linhagem Germinativa/genética , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Genes BRCA1 , Estudo de Associação Genômica Ampla , Humanos , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Característica Quantitativa Herdável , Proteína p107 Retinoblastoma-Like/genética , Transdução de Sinais/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
OBJECTIVE: Biological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that accompany malignant transformation in CRC and to identify clinically relevant biomarkers through spatial profiling of pT1 CRC samples. DESIGN: We employed digital spatial profiling (GeoMx) on eight pT1 CRCs to study gene expression in the epithelial and stromal segments across regions of distinct histology, including normal mucosa, low-grade and high-grade dysplasia and cancer. Consecutive histology sections were profiled by imaging mass cytometry to reveal immune contextures. Finally, publicly available single-cell RNA-sequencing data was analysed to determine the cellular origin of relevant transcripts. RESULTS: Comparison of gene expression between regions within pT1 CRC samples identified differentially expressed genes in the epithelium (n=1394 genes) and the stromal segments (n=1145 genes) across distinct histologies. Pathway analysis identified an early onset of inflammatory responses during malignant transformation, typified by upregulation of gene signatures such as innate immune sensing. We detected increased infiltration of myeloid cells and a shift in macrophage populations from pro-inflammatory HLA-DR+CD204- macrophages to HLA-DR-CD204+ immune-suppressive subsets from normal tissue through dysplasia to cancer, accompanied by the upregulation of the CD47/SIRPα 'don't eat me signal'. CONCLUSION: Spatial profiling revealed the molecular and immunological landscape of CRC tumourigenesis at early disease stage. We identified biomarkers with strong association with disease progression as well as targetable immune processes that are exploitable in a clinical setting.
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Neoplasias Colorretais , Transcriptoma , Humanos , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Transformação Celular Neoplásica/genética , BiomarcadoresRESUMO
A cancer immune phenotype characterized by an active T-helper 1 (Th1)/cytotoxic response is associated with responsiveness to immunotherapy and favorable prognosis across different tumors. However, in some cancers, such an intratumoral immune activation does not confer protection from progression or relapse. Defining mechanisms associated with immune evasion is imperative to refine stratification algorithms, to guide treatment decisions and to identify candidates for immune-targeted therapy. Molecular alterations governing mechanisms for immune exclusion are still largely unknown. The availability of large genomic datasets offers an opportunity to ascertain key determinants of differential intratumoral immune response. We follow a network-based protocol to identify transcription regulators (TRs) associated with poor immunologic antitumor activity. We use a consensus of four different pipelines consisting of two state-of-the-art gene regulatory network inference techniques, regularized gradient boosting machines and ARACNE to determine TR regulons, and three separate enrichment techniques, including fast gene set enrichment analysis, gene set variation analysis and virtual inference of protein activity by enriched regulon analysis to identify the most important TRs affecting immunologic antitumor activity. These TRs, referred to as master regulators (MRs), are unique to immune-silent and immune-active tumors, respectively. We validated the MRs coherently associated with the immune-silent phenotype across cancers in The Cancer Genome Atlas and a series of additional datasets in the Prediction of Clinical Outcomes from Genomic Profiles repository. A downstream analysis of MRs specific to the immune-silent phenotype resulted in the identification of several enriched candidate pathways, including NOTCH1, TGF-$\beta $, Interleukin-1 and TNF-$\alpha $ signaling pathways. TGFB1I1 emerged as one of the main negative immune modulators preventing the favorable effects of a Th1/cytotoxic response.
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Biomarcadores Tumorais , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias/etiologia , Neoplasias/metabolismo , Fenótipo , Biologia Computacional/métodos , Bases de Dados Genéticas , Suscetibilidade a Doenças/imunologia , Perfilação da Expressão Gênica/métodos , Humanos , Imunofenotipagem , Reprodutibilidade dos Testes , Transdução de Sinais , TranscriptomaRESUMO
Sepsis is an aberrant systemic inflammatory response mediated by the acute activation of the innate immune system. Neutrophils are important contributors to the innate immune response that controls the infection, but harbour the risk of collateral tissue damage such as thrombosis and organ dysfunction. A better understanding of the modulations of cellular processes in neutrophils and other blood cells during sepsis is needed and can be initiated via transcriptomic profile investigations. To that point, the growing repertoire of publicly accessible transcriptomic datasets serves as a valuable resource for discovering and/or assessing the robustness of biomarkers. We employed systematic literature mining, reductionist approach to gene expression profile and empirical in vitro work to highlight the role of a Nudix hydrolase family member, NUDT16, in sepsis. The relevance and implication of the expression of NUDT16 under septic conditions and the putative functional roles of this enzyme are discussed.
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Sepse , Transcriptoma , Humanos , Pirofosfatases , Sepse/genética , Transcriptoma/genéticaRESUMO
MOTIVATION: We previously described the construction and characterization of fixed reusable blood transcriptional module repertoires. More recently we released a third iteration ('BloodGen3' module repertoire) that comprises 382 functionally annotated modules and encompasses 14 168 transcripts. Custom bioinformatic tools are needed to support downstream analysis, visualization and interpretation relying on such fixed module repertoires. RESULTS: We have developed and describe here an R package, BloodGen3Module. The functions of our package permit group comparison analyses to be performed at the module-level, and to display the results as annotated fingerprint grid plots. A parallel workflow for computing module repertoire changes for individual samples rather than groups of samples is also available; these results are displayed as fingerprint heatmaps. An illustrative case is used to demonstrate the steps involved in generating blood transcriptome repertoire fingerprints of septic patients. Taken together, this resource could facilitate the analysis and interpretation of changes in blood transcript abundance observed across a wide range of pathological and physiological states. AVAILABILITY AND IMPLEMENTATION: The BloodGen3Module package and documentation are freely available from Github: https://github.com/Drinchai/BloodGen3Module. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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BACKGROUND: Advances in our understanding of the tumor microenvironment have radically changed the cancer field, highlighting the emerging need for biomarkers of an active, favorable tumor immune phenotype to aid treatment stratification and clinical prognostication. Numerous immune-related gene signatures have been defined; however, their prognostic value is often limited to one or few cancer types. Moreover, the area of non-coding RNA as biomarkers remains largely unexplored although their number and biological roles are rapidly expanding. METHODS: We developed a multi-step process to identify immune-related long non-coding RNA signatures with prognostic connotation in multiple TCGA solid cancer datasets. RESULTS: Using the breast cancer dataset as a discovery cohort we found 2988 differentially expressed lncRNAs between immune favorable and unfavorable tumors, as defined by the immunologic constant of rejection (ICR) gene signature. Mapping of the lncRNAs to a coding-non-coding network identified 127 proxy protein-coding genes that are enriched in immune-related diseases and functions. Next, we defined two distinct 20-lncRNA prognostic signatures that show a stronger effect on overall survival than the ICR signature in multiple solid cancers. Furthermore, we found a 3 lncRNA signature that demonstrated prognostic significance across 5 solid cancer types with a stronger association with clinical outcome than ICR. Moreover, this 3 lncRNA signature showed additional prognostic significance in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to ICR. CONCLUSION: We identified an immune-related 3-lncRNA signature with prognostic connotation in multiple solid cancer types which performed equally well and in some cases better than the 20-gene ICR signature, indicating that it could be used as a minimal informative signature for clinical implementation.
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Carcinoma de Células Escamosas , RNA Longo não Codificante , Neoplasias do Colo do Útero , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Microambiente Tumoral , Neoplasias do Colo do Útero/genéticaRESUMO
Viruses are the second leading cause of cancer worldwide, and human papillomavirus (HPV)-associated head and neck cancers are increasing in incidence in the United States. HPV preferentially infects the crypts of the tonsils rather than the surface epithelium. The present study sought to characterize the unique microenvironment within the crypts to better understand the viral tropism of HPV to a lymphoid-rich organ. Laser-capture microdissection of distinct anatomic areas (crypts, surface epithelium, and germinal centers) of the tonsil, coupled with transcriptional analysis and multiparameter immunofluorescence staining demonstrated that the tonsillar crypts are enriched with myeloid populations that co-express multiple canonical and noncanonical immune checkpoints, including PD-L1, CTLA-4, HAVCR2 (TIM-3), ADORA2A, IDO1, BTLA, LGALS3, CDH1, CEACAM1, PVR, and C10orf54 (VISTA). The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.
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Alphapapillomavirus/fisiologia , Células Mieloides/patologia , Células Mieloides/virologia , Tonsila Palatina/patologia , Tonsila Palatina/virologia , Tropismo Viral/fisiologia , Antígenos CD/metabolismo , Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Moléculas de Adesão Celular/metabolismo , Epitélio/patologia , Epitélio/virologia , Centro Germinativo/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Microdissecção e Captura a Laser , Monócitos/patologia , Receptores Virais/metabolismo , Transcriptoma/genéticaRESUMO
The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients. Contingency tables were constructed and a χ2 test was used to test for statistical significance. Odds ratios with 95% confidence intervals were calculated. The presence of tumor infiltrating lymphocytes and a mucinous phenotype (>50% mucinous surface area) were strongly correlated with CMS1 (p < 0.001 and p = 0.008) and CRIS-A (p = 0.006 and p < 0.001). The presence of mucus (≥ 10%) was associated with CMS3: mucus was present in 64.1% of all CMS3 tumors (p < 0.001). Although a clear association between tumor-stroma ratio and CMS4 was established in this study (p = 0.006), still 32 out of 61 (52.5%) CMS4 tumors were scored as stroma-low, indicating that CMS4 tumors cannot be identified solely based on stromal content. Higher budding counts were seen in CMS4 and CRIS-B tumors (p = 0.045 and p = 0.046). No other associations of the measured parameters were seen for any of the other CRIS subtypes. Our analysis revealed clear associations between histopathologic features and CMS or CRIS subtypes. However, identification of distinct molecular subtypes solely based on histopathology proved to be infeasible. Combining both molecular and morphologic features could potentially improve patient stratification.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Hematoxilina , Amarelo de Eosina-(YS) , Neoplasias do Colo/genética , Neoplasias Colorretais/patologia , Expressão Gênica , RNA , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: The balance between immune-stimulatory and immune-suppressive mechanisms in the tumour microenvironment is associated with tumour rejection and can predict the efficacy of immune checkpoint-inhibition therapies. METHODS: We consider the observed differences between the transcriptional programmes associated with cancer types where the levels of immune infiltration predict a favourable prognosis versus those in which the immune infiltration predicts an unfavourable prognosis and defined a score named Mediators of Immune Response Against Cancer in soLid microEnvironments (MIRACLE). MIRACLE deconvolves T cell infiltration, from inhibitory mechanisms, such as TGFß, EMT and PI3Kγ signatures. RESULTS: Our score outperforms current state-of-the-art immune signatures as a predictive marker of survival in TCGA (n = 9305, HR: 0.043, p value: 6.7 × 10-36). In a validation cohort (n = 7623), MIRACLE predicts better survival compared to other immune metrics (HR: 0.1985, p value: 2.73 × 10-38). MIRACLE also predicts response to checkpoint-inhibitor therapies (n = 333). The tumour-intrinsic factors inversely associated with the reported score such as EGFR, PRKAR1A and MAP3K1 are frequently associated with immune-suppressive phenotypes. CONCLUSIONS: The association of cancer outcome with the level of infiltrating immune cells is mediated by the balance of activatory and suppressive factors. MIRACLE accounts for this balance and predicts favourable cancer outcomes.
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Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Estudos de Coortes , Bases de Dados Genéticas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Vigilância Imunológica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Análise de SobrevidaRESUMO
According to publicly available transcriptome datasets, the abundance of Annexin A3 (ANXA3) is robustly increased during the course of sepsis; however, no studies have examined the biological significance or clinical relevance of ANXA3 in this pathology. Here we explored this interpretation gap and identified possible directions for future research. Based on reference transcriptome datasets, we found that ANXA3 expression is restricted to neutrophils, is upregulated in vitro after exposure to plasma obtained from septic patients, and is associated with adverse clinical outcomes. Secondly, an increase in ANXA3 transcript abundance was also observed in vivo, in the blood of septic patients in multiple independent studies. ANXA3 is known to mediate calcium-dependent granules-phagosome fusion in support of microbicidal activity in neutrophils. More recent work has also shown that ANXA3 enhances proliferation and survival of tumour cells via a Caspase-3-dependent mechanism. And this same molecule is also known to play a critical role in regulation of apoptotic events in neutrophils. Thus, we posit that during sepsis ANXA3 might either play a beneficial role, by facilitating microbial clearance and resolution of the infection; or a detrimental role, by prolonging neutrophil survival, which is known to contribute to sepsis-mediated organ damage.
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Anexina A3/metabolismo , Neutrófilos/imunologia , Sepse/imunologia , Acesso à Informação , Animais , Anexina A3/genética , Caspase 3/metabolismo , Conjuntos de Dados como Assunto , Humanos , Fagossomos/metabolismo , TranscriptomaRESUMO
Human leukocyte antigen G (HLA-G), known as a central protein in providing immune tolerance to the fetus in pregnant women, is also studied for a possible role in tumor development. Many studies have claimed HLA-G as a new immune checkpoint in cancer. Therefore, HLA-G and its receptors might be targets for immune checkpoint blockade in cancer immunotherapy. In order to substantiate that HLA-G is indeed an immune checkpoint in cancer, two important questions need to be answered: (1) To what extent is HLA-G expressed in the tumor by cancer cells? and (2) What is the function of HLA-G in cancer immune evasion? In this review, we discuss these questions. We agree that HLA-G is a potentially new immune checkpoint in cancer, but additional evidence is required to show the extent of intra-tumor and inter-tumor expression. These studies should focus on tumor expression patterns of the seven different HLA-G isoforms and of the receptors for HLA-G. Furthermore, specific roles for the different HLA-G isoforms should be established.
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Antígenos HLA-G/imunologia , Antígenos HLA-G/metabolismo , Neoplasias/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Antígenos HLA-G/genética , Humanos , Evasão da Resposta Imune/imunologia , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Imunoterapia/tendências , Isoformas de Proteínas/metabolismoRESUMO
The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate subtherapeutic dose and an incomplete therapeutic dose. The two models are based on cycles of insufficient treatment of Plasmodium berghei-infected mice: repeated inadequate treatment associated with a subtherapeutic dose (RIaT) (0.1 mg kg-1 of body weight) and repeated incomplete treatment with a therapeutic dose (RIcT) (14.4 mg kg-1 of body weight). The number of treatment cycles for the development of a stable resistance phenotype during RIaT was 2.00 ± 0.00 cycles (n = 9), which is not statistically different from that during RIcT (2.57 ± 0.85 cycles; combined n = 14; P = 0.0591). All mutations underlying atovaquone resistance selected by RIaT (M133I, T142N, and L144S) were found to be in the Qo1 (quinone binding 1) domain of the mitochondrial cytochrome b gene, in contrast to those selected by RIcT (Y268N/C, L271V, K272R, and V284F) in the Qo2 domain or its neighboring sixth transmembrane region. Exposure of mixed populations of resistant parasites from RIaT to the higher therapeutic dose of RIcT revealed further insights into the dynamics of within-host selection of resistance to antimalarial drugs. These results suggest that both inadequate subtherapeutic doses and incomplete therapeutic doses in malaria treatment pose similar threats to the emergence of drug resistance. RIcT and RIaT could be developed as useful tools to predict the potential emergence of resistance to newly introduced and less-understood antimalarials.
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Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Citocromos b/genética , Resistência a Medicamentos/genética , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Animais , Cálculos da Dosagem de Medicamento , Malária/parasitologia , Erros de Medicação , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/genéticaRESUMO
The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of colorectal cancer (CRC) has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs) based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.
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Neoplasias Colorretais/imunologia , Sistema Imunitário/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Metástase Neoplásica , Microambiente TumoralRESUMO
The evolutionary selection of malaria parasites within individual hosts is an important factor in the emergence of drug resistance but is still not well understood. We have examined the selection process for drug resistance in the mouse malaria agent Plasmodium berghei and compared the dynamics of the selection for atovaquone and pyrimethamine. Resistance to these drugs has been shown to be associated with genetic lesions in the dihydrofolate reductase gene in the case of pyrimethamine and in the mitochondrial cytochrome b gene for atovaquone. A mouse malaria model for the selection of drug resistance, based on repeated incomplete treatment (RICT) with a therapeutic dose of antimalarial drugs, was established. The number of treatment cycles for the development of stable resistance to atovaquone (2.47 ± 0.70; n = 19) was found to be significantly lower than for pyrimethamine (5.44 ± 1.46; n = 16; P < 0.0001), even when the parental P. berghei Leiden strain was cloned prior to the resistance selection. Similar results were obtained with P. berghei Edinburgh. Mutational changes underlying the resistance were identified to be S110N in dihydrofolate reductase for pyrimethamine and Y268N, Y268C, Y268S, L271V-K272R, and G280D in cytochrome b for atovaquone. These results are consistent with the rate of mitochondrial DNA mutation being higher than that in the nucleus and suggest that mutation leading to pyrimethamine resistance is not a rare event.
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Antimaláricos/farmacologia , Atovaquona/farmacologia , Citocromos b/genética , Resistência a Medicamentos/genética , Plasmodium berghei/efeitos dos fármacos , Pirimetamina/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Substituição de Aminoácidos , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/enzimologia , Núcleo Celular/genética , Citocromos b/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Expressão Gênica , Interações Hospedeiro-Parasita , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/genética , Taxa de Mutação , Testes de Sensibilidade Parasitária , Plasmodium berghei/enzimologia , Plasmodium berghei/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Seleção Genética , Tetra-Hidrofolato Desidrogenase/metabolismo , Falha de TratamentoRESUMO
Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8+ T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8+ T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling. Exposure of non-polarized macrophages to activated T cell supernatant and tumor lysate recapitulates the late-stage activated and tumoricidal phenotype in vitro. The transcriptomic signature of these macrophages is also detected in a similar macrophage population present in human tumors and coincides with clinical response to immune checkpoint inhibitors. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies.
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Linfócitos T CD8-Positivos , Imunoterapia , Macrófagos , Animais , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Camundongos , Humanos , Macrófagos/imunologia , Receptores CCR5/metabolismo , Receptores CCR5/genética , Camundongos Endogâmicos C57BL , Ativação de Macrófagos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Ativação Linfocitária/imunologia , Feminino , Microambiente Tumoral/imunologiaRESUMO
Development and progression of malignancies are accompanied and influenced by alterations in the surrounding immune microenvironment. Understanding the cellular and molecular interactions between immune cells and cancer cells has not only provided important fundamental insights into the disease, but has also led to the development of new immunotherapies. The C-type lectin Dendritic Cell ImmunoReceptor (DCIR) is primarily expressed by myeloid cells and is an important regulator of immune homeostasis, as demonstrated in various autoimmune, infectious and inflammatory contexts. Yet, the impact of DCIR on cancer development remains largely unknown. Analysis of available transcriptomic data of colorectal cancer (CRC) patients revealed that high DCIR gene expression is associated with improved patients' survival, immunologically "hot" tumors and high immunologic constant of rejection, thus arguing for a protective and immunoregulatory role of DCIR in CRC. In line with these correlative data, we found that deficiency of DCIR1, the murine homologue of human DCIR, leads to the development of significantly larger tumors in an orthotopic murine model of CRC. This phenotype is accompanied by an altered phenotype of tumor-associated macrophages (TAMs) and a reduction in the percentage of activated effector CD4+ and CD8+ T cells in CRC tumors of DCIR1-deficient mice. Overall, our results show that DCIR promotes antitumor immunity in CRC, making it an attractive target for the future development of immunotherapies to fight the second deadliest cancer in the world.
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Linfócitos T CD8-Positivos , Neoplasias Colorretais , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/metabolismo , Células Dendríticas , Imunidade , Lectinas Tipo C/metabolismo , Microambiente TumoralRESUMO
Background: Colon cancer is a heterogeneous disease and consists of various molecular subtypes. Despite advances in high-throughput expression profiling, limitations remain in predicting clinical outcome and assigning specific treatment to individual cases. Tumor-immune interactions play a critical role, with tumors that activate the immune system having better outcome for the patient. The localization of T cells within tumor epithelium, to enable direct contact, is essential for antitumor function, but bulk DNA/RNA sequencing data lacks spatial distribution information. In this study, we provide spatial T cell tumor distribution and connect these data with previously determined genomic data in the AC-ICAM colon cancer patient cohort. Methods: Colon cancer patients (n=90) with transcriptome data available were selected. We used a custom multiplex immunofluorescence assay on colon tumor tissue sections for quantifying T cell subsets spatial distribution in the tumor microenvironment, in terms of cell number, location, mutual distance, and distance to tumor cells. Statistical analyses included the previously determined Immunologic Constant of Rejection (ICR) transcriptome correlation and patient survival, revealing potential prognostic value in T cell spatial distribution. Results: T cell phenotypes were characterized and CD3+CD8-FoxP3- T cells were found to be the predominant tumor-infiltrating subtype while CD3+FoxP3+ T cells and CD3+CD8+ T cells showed similar densities. Spatial distribution analysis elucidated that proliferative T cells, characterized by Ki67 expression, and Granzyme B-expressing T cells were predominantly located within the tumor epithelium. We demonstrated an increase in immune cell density and a decrease in the distance of CD3+CD8+ T cells to the nearest tumor cell, in the immune active, ICR High, immune subtypes. Higher densities of stromal CD3+FoxP3+ T cells showed enhanced survival outcomes, and patients exhibited superior clinical benefits when greater spatial distances were observed between CD3+CD8-FoxP3- or CD3+CD8+ T cells and CD3+FoxP3+ T cells. Conclusion: Our study's in-depth analysis of the spatial distribution and densities of major T cell subtypes within the tumor microenvironment has provided valuable information that paves the way for further research into the intricate relationships between immune cells and colon cancer development.
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Linfócitos T CD8-Positivos , Neoplasias do Colo , Humanos , Prognóstico , Subpopulações de Linfócitos T , Neoplasias do Colo/patologia , Fatores de Transcrição Forkhead/análise , Microambiente TumoralRESUMO
BACKGROUND: Chordomas are rare cancers from the axial skeleton which present a challenging clinical management with limited treatment options due to their anatomical location. In recent years, a few clinical trials demonstrated that chordomas can respond to immunotherapy. However, an in-depth portrayal of chordoma immunity and its association with clinical parameters is still lacking. METHODS: We present a comprehensive characterization of immunological features of 76 chordomas through application of a multimodal approach. Transcriptomic profiling of 20 chordomas was performed to inform on the activity of immune-related genes through the immunologic constant of rejection (ICR) signature. Multidimensional immunophenotyping through imaging mass cytometry was applied to provide insights in the different immune contextures of 32 chordomas. T cell infiltration was further evaluated in all 76 patients by means of multispectral immunofluorescence and then associated with clinical parameters through univariate and multivariate Cox proportional hazard models as well as Kaplan-Meier estimates. Moreover, distinct expression patterns of human leukocyte antigen (HLA) class I were assessed by immunohistochemical staining in all 76 patients. Finally, clonal enrichment of the T cell receptor (TCR) was sought through profiling of the variable region of TCRB locus of 24 patients. RESULTS: Chordomas generally presented an immune "hot" microenvironment in comparison to other sarcomas, as indicated by the ICR transcriptional signature. We identified two distinct groups of chordomas based on T cell infiltration which were independent from clinical parameters. The highly infiltrated group was further characterized by high dendritic cell infiltration and the presence of multicellular immune aggregates in tumors, whereas low T cell infiltration was associated with lower overall cell densities of immune and stromal cells. Interestingly, patients with higher T cell infiltration displayed a more pronounced clonal enrichment of the TCR repertoire compared with those with low T cell counts. Furthermore, we observed that the majority of chordomas maintained HLA class I expression. CONCLUSION: Our findings shed light on the natural immunity against chordomas through the identification of distinct immune contextures. Understanding their immune landscape could guide the development and application of immunotherapies in a tailored manner, ultimately leading to an improved clinical outcome for patients with chordoma.
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Cordoma , Humanos , Cordoma/genética , Cordoma/patologia , Cordoma/terapia , Perfilação da Expressão Gênica , Receptores de Antígenos de Linfócitos T/genética , Microambiente TumoralRESUMO
The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.