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1.
Gastroenterology ; 166(5): 787-801.e11, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38244726

RESUMO

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.


Assuntos
Antígenos de Neoplasias , Neoplasias Colorretais Hereditárias sem Polipose , Sequenciamento do Exoma , Mutação da Fase de Leitura , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Feminino , Mutação , Masculino , Pessoa de Meia-Idade , Reparo de Erro de Pareamento de DNA/genética , Repetições de Microssatélites , Instabilidade de Microssatélites , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/prevenção & controle , Adulto , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico
2.
J Chem Inf Model ; 64(5): 1730-1750, 2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38415656

RESUMO

The recognition of peptides bound to class I major histocompatibility complex (MHC-I) receptors by T-cell receptors (TCRs) is a determinant of triggering the adaptive immune response. While the exact molecular features that drive the TCR recognition are still unknown, studies have suggested that the geometry of the joint peptide-MHC (pMHC) structure plays an important role. As such, there is a definite need for methods and tools that accurately predict the structure of the peptide bound to the MHC-I receptor. In the past few years, many pMHC structural modeling tools have emerged that provide high-quality modeled structures in the general case. However, there are numerous instances of non-canonical cases in the immunopeptidome that the majority of pMHC modeling tools do not attend to, most notably, peptides that exhibit non-standard amino acids and post-translational modifications (PTMs) or peptides that assume non-canonical geometries in the MHC binding cleft. Such chemical and structural properties have been shown to be present in neoantigens; therefore, accurate structural modeling of these instances can be vital for cancer immunotherapy. To this end, we have developed APE-Gen2.0, a tool that improves upon its predecessor and other pMHC modeling tools, both in terms of modeling accuracy and the available modeling range of non-canonical peptide cases. Some of the improvements include (i) the ability to model peptides that have different types of PTMs such as phosphorylation, nitration, and citrullination; (ii) a new and improved anchor identification routine in order to identify and model peptides that exhibit a non-canonical anchor conformation; and (iii) a web server that provides a platform for easy and accessible pMHC modeling. We further show that structures predicted by APE-Gen2.0 can be used to assess the effects that PTMs have in binding affinity in a more accurate manner than just using solely the sequence of the peptide. APE-Gen2.0 is freely available at https://apegen.kavrakilab.org.


Assuntos
Hominidae , Peptídeos , Animais , Peptídeos/química , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Processamento de Proteína Pós-Traducional , Hominidae/metabolismo , Ligação Proteica
3.
Proc Natl Acad Sci U S A ; 117(48): 30610-30618, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33184174

RESUMO

Peptide binding to major histocompatibility complexes (MHCs) is a central component of the immune system, and understanding the mechanism behind stable peptide-MHC binding will aid the development of immunotherapies. While MHC binding is mostly influenced by the identity of the so-called anchor positions of the peptide, secondary interactions from nonanchor positions are known to play a role in complex stability. However, current MHC-binding prediction methods lack an analysis of the major conformational states and might underestimate the impact of secondary interactions. In this work, we present an atomically detailed analysis of peptide-MHC binding that can reveal the contributions of any interaction toward stability. We propose a simulation framework that uses both umbrella sampling and adaptive sampling to generate a Markov state model (MSM) for a coronavirus-derived peptide (QFKDNVILL), bound to one of the most prevalent MHC receptors in humans (HLA-A24:02). While our model reaffirms the importance of the anchor positions of the peptide in establishing stable interactions, our model also reveals the underestimated importance of position 4 (p4), a nonanchor position. We confirmed our results by simulating the impact of specific peptide mutations and validated these predictions through competitive binding assays. By comparing the MSM of the wild-type system with those of the D4A and D4P mutations, our modeling reveals stark differences in unbinding pathways. The analysis presented here can be applied to any peptide-MHC complex of interest with a structural model as input, representing an important step toward comprehensive modeling of the MHC class I pathway.


Assuntos
Complexo Principal de Histocompatibilidade , Cadeias de Markov , Modelos Moleculares , Peptídeos/metabolismo , Alanina/genética , Ligação Competitiva , Simulação por Computador , Análise Mutacional de DNA , Mutação/genética , Prolina/metabolismo , Ligação Proteica
4.
Proc Natl Acad Sci U S A ; 113(21): 5999-6004, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27162338

RESUMO

Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and ß2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.


Assuntos
Apresentação de Antígeno , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Transativadores/imunologia , Ativação Transcricional/imunologia , Evasão Tumoral , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Transativadores/genética , Microglobulina beta-2/genética , Microglobulina beta-2/imunologia
5.
Cancer Treat Res ; 167: 371-416, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26601872

RESUMO

The past several years can be considered a renaissance era in the treatment of metastatic melanoma. Following a 30-year stretch in which oncologists barely put a dent in a very grim overall survival (OS) rate for these patients, things have rapidly changed course with the recent approval of three new melanoma drugs by the FDA. Both oncogene-targeted therapy and immune checkpoint blockade approaches have shown remarkable efficacy in a subset of melanoma patients and have clearly been game-changers in terms of clinical impact. However, most patients still succumb to their disease, and thus, there remains an urgent need to improve upon current therapies. Fortunately, innovations in molecular medicine have led to many silent gains that have greatly increased our understanding of the nature of cancer biology as well as the complex interactions between tumors and the immune system. They have also allowed for the first time a detailed understanding of an individual patient's cancer at the genomic and proteomic level. This information is now starting to be employed at all stages of cancer treatment, including diagnosis, choice of drug therapy, treatment monitoring, and analysis of resistance mechanisms upon recurrence. This new era of personalized medicine will foreseeably lead to paradigm shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. Advances in xenograft technology will also allow for the testing of drug combinations using in vivo models, a truly necessary development as the number of new drugs needing to be tested is predicted to skyrocket in the coming years. This chapter will provide an overview of recent technological developments in cancer research, and how they are expected to impact future diagnosis, monitoring, and development of novel treatments for metastatic melanoma.


Assuntos
Melanoma/terapia , Transferência Adotiva , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/imunologia , Humanos , Melanoma/secundário , Terapia de Alvo Molecular , Medicina de Precisão , Linfócitos T/imunologia
6.
Annu Rev Med ; 64: 71-90, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23092383

RESUMO

For many years, immunotherapeutic approaches for cancer held more promise than actual clinical benefit for the majority of patients. However, several recent key advances in tumor immunology have now turned the tide in favor of immunotherapy for the treatment of many different cancer types. In this review, we describe four of the most effective immunotherapeutic approaches currently used in the clinic: cancer vaccines, immunostimulatory agents, adoptive T cell therapy, and immune checkpoint blockade. In addition, we discuss some of the most promising future strategies that aim to utilize multiple immunotherapies or combine them with other approaches to more effectively target cancer.


Assuntos
Vacinas Anticâncer/uso terapêutico , Sistema Imunitário , Imunoterapia/métodos , Neoplasias/terapia , Humanos , Neoplasias/imunologia
7.
Blood ; 120(23): 4533-43, 2012 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-22936666

RESUMO

Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to provide a potent costimulatory signal to T cells. The combination of dasatinib and anti-OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-γ-induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration. These studies delineate a strategy by which targeted therapy and immunotherapy may be combined to achieve superior antitumor responses in cancer patients.


Assuntos
Anticorpos/farmacologia , Mastocitoma/tratamento farmacológico , Pirimidinas/farmacologia , Linfócitos T/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Anticorpos/administração & dosagem , Anticorpos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Quimiocinas/genética , Quimiocinas/imunologia , Dasatinibe , Esquema de Medicação , Sinergismo Farmacológico , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon gama/imunologia , Interferon gama/metabolismo , Mastocitoma/genética , Mastocitoma/imunologia , Camundongos , Camundongos Endogâmicos DBA , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/imunologia , Pirimidinas/administração & dosagem , Receptores OX40/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Tiazóis/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Clin Chem Lab Med ; 52(9): 1357-65, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24646790

RESUMO

BACKGROUND: CD4+CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) accumulate in malignant tumors and negatively regulate antitumor immunity. However, the clinical significance of Tregs in HCC remains unclear. To determine the prognostic value of Tregs, we conducted a retrospective study on 264 patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who underwent transcatheter arterial chemoembolization (TACE). METHODS: We measured the proportion of peripheral blood Tregs in 105 healthy donors and 264 HCC patients (stage B) prior to and following TACE between 2005 and 2007. All HCC patients were followed up until December 2012. The correlations between the proportion of Tregs and clinicopathologic factors were analyzed, and long-term survival rate after TACE according to the percentage of Tregs was assessed by univariate and multivariate analyses. RESULTS: The 1-, 2-, 3-, 4- and 5-year cumulative survival rates were 62.1%, 32.6%, 16.5%, 10.4% and 6.9%, respectively, and the median survival time was 19.0 months. The cumulative survival rate was significantly lower in patients with higher levels of peripheral blood Treg cells compared to those with lower Treg levels (p<0.001). Furthermore, we found that both pre- and post-TACE peripheral blood Treg levels showed significant negative association with overall survival time (p<0.001). CONCLUSIONS: Elevated peripheral blood CD4+CD25+FOXP3+Treg levels are an independent predictive factor of poor survival after TACE for HCC (stage B) patients. These results suggest that targeting Tregs may improve patient outcomes, and provide a strong rationale for testing these approaches in future immunotherapy-based clinical trials.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/metabolismo , Contagem de Linfócito CD4 , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Adulto Jovem
9.
Cancer Res ; 84(7): 965-976, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38266066

RESUMO

Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification of alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators of tumor-intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations with immune checkpoint inhibitors. Some success has been observed in early clinical studies that combined immunotherapy with agents targeting DNA methylation and histone modification; however, less is known about chromatin remodeler-targeted therapies. Here, we provide a discussion on the regulation of tumor immunogenicity by the chromatin remodeling SWI/SNF complex through multiple mechanisms associated with immunotherapy response that broadly include IFN signaling, DNA damage, mismatch repair, regulation of oncogenic programs, and polycomb-repressive complex antagonism. Context-dependent targeting of SWI/SNF subunits can elicit opportunities for synthetic lethality and reduce T-cell exhaustion. In summary, alongside the significance of SWI/SNF subunits in predicting immunotherapy outcomes, their ability to modulate the tumor immune landscape offers opportunities for therapeutic intervention.


Assuntos
Cromatina , Neoplasias , Humanos , Fatores de Transcrição/metabolismo , Proteínas Cromossômicas não Histona/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/genética , Neoplasias/terapia , Montagem e Desmontagem da Cromatina , Microambiente Tumoral
10.
Front Oncol ; 14: 1403052, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38912065

RESUMO

Introduction: Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain-containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists. Methods: The aim of this study was to evaluate the cellular function and downstream genomic targets of VGLL1 in placental, pancreatic, and breast cancer cells. Functional assays were employed to assess the role of VGLL1 in cellular invasion and proliferation, and ChIP-seq and RNAseq assays were performed to identify VGLL1 target genes and potential impact using pathway analysis. Results: ChIP-seq analysis identified eight transcription factors with a VGLL1-binding motif that were common between all three cell types, including TEAD1-4, AP-1, and GATA6, and revealed ~3,000 shared genes with which VGLL1 interacts. Furthermore, increased VGLL1 expression led to an enhancement of cell invasion and proliferation, which was supported by RNAseq analysis showing transcriptional changes in several genes known to be involved in these processes. Discussion: This work expands our mechanistic understanding of VGLL1 function in tumor cells and provides a strong rationale for developing VGLL1-targeted therapies for treating cancer patients.

11.
Cancer Immunol Res ; 12(5): 530-543, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38363296

RESUMO

Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.


Assuntos
Sinapses Imunológicas , Receptores de Antígenos de Linfócitos T , Linfócitos T , Humanos , Células Apresentadoras de Antígenos/imunologia , Linhagem Celular Tumoral , Biblioteca Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 16/genética , Sinapses Imunológicas/imunologia , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/imunologia , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia
12.
Biochim Biophys Acta Rev Cancer ; 1878(3): 188892, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37004960

RESUMO

Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as a driver of tumor progression, VGLL1 has become a target of interest for potential anticancer therapies. In this review, we discuss VGLL1 from an evolutionary perspective, contrast its role in placental and tumor development, summarize the current knowledge of how signaling pathways can modulate VGLL1 function, and discuss potential approaches for targeting VGLL1 therapeutically.


Assuntos
Proteínas de Ligação a DNA , Neoplasias , Animais , Feminino , Humanos , Gravidez , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Placenta/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição de Domínio TEA , Neoplasias/genética , Mamíferos/metabolismo
13.
bioRxiv ; 2023 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-36993682

RESUMO

Personalized immunotherapy holds the promise of revolutionizing cancer prevention and treatment. However, selecting HLA-bound peptide targets that are specific to patient tumors has been challenging due to a lack of patient-specific antigen presentation models. Here, we present epiNB, a white-box, positive-example-only, semi-supervised method based on Naïve Bayes formulation, with information content-based feature selection, to achieve accurate modeling using Mass Spectrometry data eluted from mono-allelic cell lines and patient-derived cell lines. In addition to achieving state-of-the-art accuracy, epiNB yields novel insights into the structural properties, such as interactions of peptide positions, that appear important for modeling personalized, tumor-specific antigen presentation. epiNB uses substantially less parameters than neural networks, does not require hyperparameter tweaking and can efficiently train and run on our web portal (https://epinbweb.streamlit.app/) or a regular PC/laptop, making it easily applicable in translational settings.

14.
Front Immunol ; 14: 1108303, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37187737

RESUMO

Introduction: Peptide-HLA class I (pHLA) complexes on the surface of tumor cells can be targeted by cytotoxic T-cells to eliminate tumors, and this is one of the bases for T-cell-based immunotherapies. However, there exist cases where therapeutic T-cells directed towards tumor pHLA complexes may also recognize pHLAs from healthy normal cells. The process where the same T-cell clone recognizes more than one pHLA is referred to as T-cell cross-reactivity and this process is driven mainly by features that make pHLAs similar to each other. T-cell cross-reactivity prediction is critical for designing T-cell-based cancer immunotherapies that are both effective and safe. Methods: Here we present PepSim, a novel score to predict T-cell cross-reactivity based on the structural and biochemical similarity of pHLAs. Results and discussion: We show our method can accurately separate cross-reactive from non-crossreactive pHLAs in a diverse set of datasets including cancer, viral, and self-peptides. PepSim can be generalized to work on any dataset of class I peptide-HLAs and is freely available as a web server at pepsim.kavrakilab.org.


Assuntos
Peptídeos , Linfócitos T Citotóxicos , Sequência de Aminoácidos , Células Clonais
15.
Vaccines (Basel) ; 11(9)2023 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-37766136

RESUMO

The epidermal growth factor receptor (EGFR) plays crucial roles in several important biological functions such as embryogenesis, epithelial tissue development, and cellular regeneration. However, in multiple solid tumor types overexpression and/or activating mutations of the EGFR gene frequently occur, thus hijacking the EGFR signaling pathway to promote tumorigenesis. Non-small cell lung cancer (NSCLC) tumors in particular often contain prevalent and shared EGFR mutations that provide an ideal source for public neoantigens (NeoAg). Studies in both humans and animal models have confirmed the immunogenicity of some of these NeoAg peptides, suggesting that they may constitute viable targets for cancer immunotherapies. Peptide vaccines targeting mutated EGFR have been tested in multiple clinical trials, demonstrating an excellent safety profile and encouraging clinical efficacy. For example, the CDX-110 (rindopepimut) NeoAg peptide vaccine derived from the EGFRvIII deletion mutant in combination with temozolomide and radiotherapy has shown efficacy in treating EGFRvIII-harboring glioblastoma multiforme (GBM) patients undergone surgery in multiple Phase I and II clinical trials. Furthermore, pilot clinical trials that have administered personalized NeoAg peptides for treating advanced-stage NSCLC patients have shown this approach to be a feasible and safe method to increase antitumor immune responses. Amongst the vaccine peptides administered, EGFR mutation-targeting NeoAgs induced the strongest T cell-mediated immune responses in patients and were also associated with objective clinical responses, implying a promising future for NeoAg peptide vaccines for treating NSCLC patients with selected EGFR mutations. The efficacy of NeoAg-targeting peptide vaccines may be further improved by combining with other modalities such as tyrosine kinase or immune checkpoint inhibitor (ICI) therapy, which are currently being tested in animal models and clinical trials. Herein, we review the most current basic and clinical research progress on EGFR-targeted peptide vaccination for the treatment of NSCLC and other solid tumor types.

16.
Front Immunol ; 14: 1237715, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37771579

RESUMO

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.


Assuntos
Anticorpos Monoclonais , Evasão Tumoral , Camundongos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Quimiocina CX3CL1/metabolismo
17.
Neuro Oncol ; 25(8): 1415-1427, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-36705543

RESUMO

BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms. METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. RESULTS: QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. CONCLUSIONS: These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.


Assuntos
Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/patologia , Camundongos Endogâmicos C57BL , Imunoterapia/métodos , Linfócitos T/metabolismo , Microambiente Tumoral
18.
PNAS Nexus ; 1(3): pgac124, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36003074

RESUMO

Human leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate CD8+ T cell-mediated immune responses to pathogen- and self-derived proteins. The HLA-I peptide-binding cleft contains dominant anchor sites in the B and F pockets that interact primarily with amino acids at peptide position 2 and the C-terminus, respectively. Nonpocket peptide-HLA interactions also contribute to peptide binding and stability, but these secondary interactions are thought to be unique to individual HLA allotypes or to specific peptide antigens. Here, we show that two positively charged residues located near the top of peptide-binding cleft facilitate interactions with negatively charged residues at position 4 of presented peptides, which occur at elevated frequencies across most HLA-I allotypes. Loss of these interactions was shown to impair HLA-I/peptide binding and complex stability, as demonstrated by both in vitro and in silico experiments. Furthermore, mutation of these Arginine-65 (R65) and/or Lysine-66 (K66) residues in HLA-A*02:01 and A*24:02 significantly reduced HLA-I cell surface expression while also reducing the diversity of the presented peptide repertoire by up to 5-fold. The impact of the R65 mutation demonstrates that nonpocket HLA-I/peptide interactions can constitute anchor motifs that exert an unexpectedly broad influence on HLA-I-mediated antigen presentation. These findings provide fundamental insights into peptide antigen binding that could broadly inform epitope discovery in the context of viral vaccine development and cancer immunotherapy.

19.
Cancer Cell ; 40(5): 509-523.e6, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35537412

RESUMO

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.


Assuntos
Colite , Neoplasias , Animais , Colite/induzido quimicamente , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia , Interleucina-6 , Camundongos , Células Mieloides , Neoplasias/tratamento farmacológico
20.
J Clin Invest ; 118(3): 1165-75, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18259609

RESUMO

A prerequisite for strong adaptive antiviral immunity is the robust initial activation of the innate immune system, which is frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor immunity is often comparatively weak, potentially due to the lack of TLR-mediated activation signals within the tumor microenvironment. To assess whether pDCs are capable of directly facilitating effective antitumor immune responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated pDCs directly into the tumor. We found that TLR9-activated pDCs induced robust, spontaneous CTL cross-priming against multiple B16 tumor antigens, leading to the regression of both treated tumors and untreated tumors at distant contralateral sites. This T cell cross-priming was mediated by conventional DCs (cDCs) and was completely dependent upon the early recruitment and activation of NK cells at the tumor site. NK cell recruitment was mediated by CCR5 via chemokines secreted by pDCs, and optimal IFN-gamma production by NK cells was mediated by OX40L expressed by pDCs. Our data thus demonstrated that activated pDCs are capable of initiating effective and systemic antitumor immunity through the orchestration of an immune cascade involving the sequential activation of NK cells, cDCs, and CD8(+) T cells.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/fisiologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/terapia , Linfócitos T/imunologia , Animais , Citocinas/fisiologia , Feminino , Interferon gama/biossíntese , Melanoma Experimental/imunologia , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Ligante OX40 , Oligodesoxirribonucleotídeos/farmacologia , Receptores CCR5/fisiologia , Receptores OX40/fisiologia , Linfócitos T Citotóxicos/imunologia , Receptor Toll-Like 9/fisiologia , Fatores de Necrose Tumoral/fisiologia
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