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PURPOSE: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. EXPERIMENTAL DESIGN: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. RESULTS: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. CONCLUSIONS: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Humanos , Feminino , Mutação , Genômica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , ExomaRESUMO
The extent to which clinical and genomic characteristics associate with prostate cancer clonal architecture, tumor evolution, and therapeutic response remains unclear. Here, we reconstructed the clonal architecture and evolutionary trajectories of 845 prostate cancer tumors with harmonized clinical and molecular data. We observed that tumors from patients who self-reported as Black had more linear and monoclonal architectures, despite these men having higher rates of biochemical recurrence. This finding contrasts with prior observations relating polyclonal architecture to adverse clinical outcomes. Additionally, we utilized a novel approach to mutational signature analysis that leverages clonal architecture to uncover additional cases of homologous recombination and mismatch repair deficiency in primary and metastatic tumors and link the origin of mutational signatures to specific subclones. Broadly, prostate cancer clonal architecture analysis reveals novel biological insights that may be immediately clinically actionable and provide multiple opportunities for subsequent investigation. Statement of significance: Tumors from patients who self-reported as Black demonstrate linear and monoclonal evolutionary trajectories yet experience higher rates of biochemical recurrence. In addition, analysis of clonal and subclonal mutational signatures identifies additional tumors with potentially actionable alterations such as deficiencies in mismatch repair and homologous recombination.
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Molecular profiling studies have enabled discoveries for metastatic prostate cancer (MPC) but have predominantly occurred in academic medical institutions and involved non-representative patient populations. We established the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to involve patients with MPC living anywhere in the US and Canada in molecular research. Here, we present results from our partnership with the first 706 MPCproject participants. While 41% of patient partners live in rural, physician-shortage, or medically underserved areas, the MPCproject has not yet achieved racial diversity, a disparity that demands new initiatives detailed herein. Among molecular data from 333 patient partners (572 samples), exome sequencing of 63 tumor and 19 cell-free DNA (cfDNA) samples recapitulated known findings in MPC, while inexpensive ultra-low-coverage sequencing of 318 cfDNA samples revealed clinically relevant AR amplifications. This study illustrates the power of a growing, longitudinal partnership with patients to generate a more representative understanding of MPC.
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Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes ß-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/ß-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/ß-catenin signaling-mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/ß-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/ß-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/ß-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth. SIGNIFICANCE: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.
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Neoplasias de Próstata Resistentes à Castração , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Via de Sinalização Wnt , Comunicação Autócrina , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-ß signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
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Antagonistas de Androgênios/uso terapêutico , Proteínas Nucleares/efeitos dos fármacos , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Repressoras/efeitos dos fármacos , Proteínas Adaptadoras de Transporte Vesicular , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Masculino , Terapia Neoadjuvante/métodos , Prostatectomia/métodos , Neoplasias da Próstata/patologia , RiscoRESUMO
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Apresentação de Antígeno/genética , Antígeno B7-H1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Citocinas/sangue , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Heterogeneidade Genética , Genoma Humano/genética , Genômica , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
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Sobrevivência Celular/genética , Fusão Gênica/genética , Neoplasias/genética , HumanosRESUMO
Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.
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Carcinoma de Células Renais/terapia , Fatores Imunológicos/imunologia , Imunoterapia , Neoplasias Renais/terapia , Microambiente Tumoral/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA/imunologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Fatores de Transcrição/imunologiaRESUMO
Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-ß signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.
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Antineoplásicos/farmacologia , Neoplasias de Próstata Resistentes à Castração/terapia , Transcrição Gênica/efeitos dos fármacos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismoRESUMO
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
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Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Checkpoint Imunológico/imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Checkpoint Imunológico/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Gênica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologiaRESUMO
We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of transforming growth factor-ß signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of TWT melanomas and revealed enrichment of DNA-repair-defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA-repair genes, and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole exomes revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.
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Distúrbios no Reparo do DNA/genética , GTP Fosfo-Hidrolases/genética , Melanoma/genética , Proteínas de Membrana/genética , Neurofibromina 1/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Reparo do DNA/genética , Predisposição Genética para Doença/genética , Humanos , Melanoma/patologia , Transdução de Sinais/genética , Neoplasias Cutâneas/patologia , Sequenciamento do ExomaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The immune composition of the tumor microenvironment influences response and resistance to immunotherapies. While numerous studies have identified somatic correlates of immune infiltration, germline features that associate with immune infiltrates in cancers remain incompletely characterized. We analyze seven million autosomal germline variants in the TCGA cohort and test for association with established immune-related phenotypes that describe the tumor immune microenvironment. We identify one SNP associated with the amount of infiltrating follicular helper T cells; 23 candidate genes, some of which are involved in cytokine-mediated signaling and others containing cancer-risk SNPs; and networks with genes that are part of the DNA repair and transcription elongation pathways. In addition, we find a positive association between polygenic risk for rheumatoid arthritis and amount of infiltrating CD8+ T cells. Overall, we identify multiple germline genetic features associated with tumor-immune phenotypes and develop a framework for probing inherited features that contribute to differences in immune infiltration.
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Células Germinativas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/genética , Neoplasias/imunologia , Doenças Autoimunes/imunologia , Reparo do DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucócitos/metabolismo , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Linfócitos T Auxiliares-Indutores/imunologia , Transcrição GênicaRESUMO
Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
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Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Mieloma Múltiplo Latente , Animais , Humanos , Camundongos , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/genética , Análise de Sequência de RNA , Microambiente Tumoral/genéticaRESUMO
PURPOSE: Heterogeneity in tumor mutational burden (TMB) quantification across sequencing platforms limits the application and further study of this potential biomarker of response to immune checkpoint inhibitors (ICI). We hypothesized that harmonization of TMB across platforms would enable integration of distinct clinical datasets to better characterize the association between TMB and ICI response. METHODS: Cohorts of NSCLC patients sequenced by one of three targeted panels or by whole exome sequencing (WES) were compared (total n=7297). TMB was calculated uniformly and compared across cohorts. TMB distributions were harmonized by applying a normal transformation followed by standardization to z-scores. In sub-cohorts of patients treated with ICIs (DFCI n=272; MSKCC n=227), the association between TMB and outcome was assessed. Durable clinical benefit (DCB) was defined as responsive/stable disease lasting ≥6 months. RESULTS: TMB values were higher in the panel cohorts than the WES cohort. Average mutation rates per gene were highly concordant across cohorts (Pearson coefficient 0.842-0.866). Subsetting the WES cohort by gene panels only partially reproduced the observed differences in TMB. Standardization of TMB into z-scores harmonized TMB distributions and enabled integration of the ICI-treated sub-cohorts. Simulations indicated that cohorts >900 are necessary for this approach. TMB did not associate with response in never smokers or patients harboring targetable driver alterations, although these analyses were under-powered. Increasing TMB thresholds increased DCB rate, but DCB rates within deciles varied. Receiver operator curves yielded an area under the curve of 0.614 with no natural inflection point. CONCLUSION: Z-score conversion harmonizes TMB values and enables integration of datasets derived from different sequencing panels. Clinical and biologic features may provide context to the clinical application of TMB, and warrant further study.
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Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Mutação/genética , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma/genética , Transcriptoma/imunologia , Sequenciamento do ExomaRESUMO
We present an in silico approach to identifying neoepitopes derived from intron retention events in tumor transcriptomes. Using mass spectrometry immunopeptidome analysis, we show that retained intron neoepitopes are processed and presented on MHC I on the surface of cancer cell lines. RNA-derived neoepitopes should be considered for prospective personalized cancer vaccine development.
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Simulação por Computador , Epitopos/genética , Íntrons/genética , Modelos Genéticos , Neoplasias/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Mapeamento de Epitopos , Epitopos/metabolismo , Humanos , Neoplasias/imunologia , Neoplasias/terapia , RNA/genéticaRESUMO
Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.