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1.
Cancer Immunol Immunother ; 73(1): 16, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38236251

RESUMO

Collagen expression and structure in the tumour microenvironment are associated with tumour development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor. LAIR-2 is a soluble homologue of LAIR-1 that competes for collagen binding. Multiple studies in mice implicate blockade of LAIR-1:collagen interaction in cancer as a promising therapeutic strategy. Here, we investigated the role of LAIR-1 in anti-tumour responses. We show that although LAIR-1 inhibits activation, proliferation, and cytokine production of mouse T cells in vitro, tumour outgrowth in LAIR-1-deficient mice did not differ from wild type mice in several in vivo tumour models. Furthermore, treatment with NC410, a LAIR-2-Fc fusion protein, did not result in increased tumour clearance in tested immunocompetent mice, which contrasts with previous data in humanized mouse models. This discrepancy may be explained by our finding that NC410 blocks human LAIR-1:collagen interaction more effectively than mouse LAIR-1:collagen interaction. Despite the lack of therapeutic impact of NC410 monotherapy, mice treated with a combination of NC410 and anti-programmed death-ligand 1 did show reduced tumour burden and increased survival. Using LAIR-1-deficient mice, we showed that this effect seemed to be dependent on the presence of LAIR-1. Taken together, our data demonstrate that the absence of LAIR-1 signalling alone is not sufficient to control tumour growth in multiple immunocompetent mouse models. However, combined targeting of LAIR-1 and PD-L1 results in increased tumour control. Thus, additional targeting of the LAIR-1:collagen pathway with NC410 is a promising approach to treating tumours where conventional immunotherapy is ineffective.


Assuntos
Antígeno B7-H1 , Neoplasias , Animais , Humanos , Camundongos , Colágeno , Modelos Animais de Doenças , Leucócitos , Ligantes , Neoplasias/tratamento farmacológico , Microambiente Tumoral
2.
Front Immunol ; 13: 1100730, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36741416

RESUMO

Oncolytic viruses are currently tested as a novel platform for cancer therapy. These viruses preferentially replicate in and kill malignant cells. Due to their microbial origin, treatment with oncolytic viruses naturally results in anti-viral responses and general immune activation. Consequently, the oncolytic virus treatment also induces anti-viral T cells. Since these can constitute the dominant activated T cell pool, monitoring of the anti-viral T cell response may aid in better understanding of the immune responses post oncolytic virotherapy. This study aimed to identify the anti-viral T cells raised by VSV-GP virotherapy in C57BL/6J mice, one of the most widely used models for preclinical studies. VSV-GP is a novel oncolytic agent that recently entered a clinical phase I study. To identify the VSV-GP epitopes to which mouse anti-viral T cells react, we used a multilevel adapted bioinformatics viral epitope prediction approach based on the tools netMHCpan, MHCflurry and netMHCstabPan, which are commonly used in neoepitope identification. Predicted viral epitopes were ranked based on consensus binding strength categories, predicted stability, and dissimilarity to the mouse proteome. The top ranked epitopes were selected and included in the peptide candidate matrix in order to use a matrix deconvolution approach. Using ELISpot, we showed which viral epitopes presented on C57BL/6J mouse MHC-I alleles H2-Db and H2-Kb trigger IFN-γ secretion due to T cell activation. Furthermore, we validated these findings using an intracellular cytokine staining. Collectively, identification of the VSV-GP T cell epitopes enables monitoring of the full range of anti-viral T cell responses upon VSV-GP virotherapy in future studies with preclinical mouse models to more comprehensively delineate anti-viral from anti-tumor T cell responses. These findings also support the development of novel VSV-GP variants expressing immunomodulatory transgenes and can improve the assessment of anti-viral immunity in preclinical models.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Camundongos , Epitopos/metabolismo , Camundongos Endogâmicos C57BL , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/fisiologia , Vírus da Estomatite Vesicular Indiana
3.
Curr Opin Immunol ; 69: 65-71, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33862306

RESUMO

Upon their activation, CD8+ T cells in the tumor micro-environment (TME) secrete cytokines such as IFNγ, TNFα, and IL-2. While over the past years a major interest has developed in the antigenic signals that induce such cytokine release, our understanding of the cells that subsequently sense these CD8+ T-cell secreted cytokines is modest. Here, we review the current insights into the spreading behavior of CD8+ T-cell-secreted cytokines in the TME. We argue for a model in which variation in the mode of cytokine secretion, cytokine half-life, receptor-mediated clearance, cytokine binding to extracellular components, and feedback or forward loops, between different cytokines or between individual tumors, sculpts the local tissue response to natural and therapy-induced T-cell activation in human cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Imunoterapia Ativa/métodos , Neoplasias/terapia , Animais , Humanos , Imunomodulação , Ativação Linfocitária , Neoplasias/imunologia , Comunicação Parácrina , Microambiente Tumoral
4.
Front Immunol ; 12: 733561, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691040

RESUMO

The tumor microenvironment (TME) is a complex structure comprised of tumor, immune and stromal cells, vasculature, and extracellular matrix (ECM). During tumor development, ECM homeostasis is dysregulated. Collagen remodeling by matrix metalloproteinases (MMPs) generates specific collagen fragments, that can be detected in the circulation of cancer patients and correlate with poor disease outcome. Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is an inhibitory collagen receptor expressed on immune cells in the TME and in the circulation. We hypothesized that in addition to ECM collagen, collagen fragments produced in cancer can mediate T cell immunosuppression through LAIR-1. Our analyses of TCGA datasets show that cancer patients with high tumor mRNA expression of MMPs, collagen I and LAIR-1 have worse overall survival. We show that in vitro generated MMP1 or MMP9 collagen I fragments bind to and trigger LAIR-1. Importantly, LAIR-1 triggering by collagen I fragments inhibits CD3 signaling and IFN-γ secretion in a T cell line. LAIR-2 is a soluble homologue of LAIR-1 with higher affinity for collagen and thereby acts as a decoy receptor. Fc fusion proteins of LAIR-2 have potential as cancer immunotherapeutic agents and are currently being tested in clinical trials. We demonstrate that collagen fragment-induced inhibition of T cell function could be reversed by LAIR-2 fusion proteins. Overall, we show that collagen fragments produced in cancer can mediate T cell suppression through LAIR-1, potentially contributing to systemic immune suppression. Blocking the interaction of LAIR-1 with collagen fragments could be an added benefit of LAIR-1-directed immunotherapy.


Assuntos
Colágeno Tipo I/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linhagem Celular , Colágeno Tipo I/genética , Matriz Extracelular/metabolismo , Humanos , Tolerância Imunológica , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias/terapia , Fragmentos de Peptídeos/genética , Ligação Proteica , Receptores Imunológicos/genética , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais , Microambiente Tumoral
5.
Elife ; 102021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34121658

RESUMO

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+ immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.


Assuntos
Colágeno/metabolismo , Fragmentos Fc das Imunoglobulinas , Imunoterapia/métodos , Receptores Imunológicos , Proteínas Recombinantes de Fusão , Animais , Antineoplásicos Imunológicos , Linhagem Celular Tumoral , Biologia Computacional , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Camundongos , Neoplasias/terapia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancers (Basel) ; 12(2)2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32102342

RESUMO

Neuroblastoma (NBL) is the most common extracranial solid tumor in childhood. Despite intense treatment, children with this high-risk disease have a poor prognosis. Immunotherapy showed a significant improvement in event-free survival in high-risk NBL patients receiving chimeric anti-GD2 in combination with cytokines and isotretinoin after myeloablative consolidation therapy. However, response to immunotherapy varies widely, and often therapy is stopped due to severe toxicities. Objective markers that help to predict which patients will respond or develop toxicity to a certain treatment are lacking. Immunotherapy guided via immune monitoring protocols will help to identify responders as early as possible, to decipher the immune response at play, and to adjust or develop new treatment strategies. In this review, we summarize recent studies investigating frequency and phenotype of immune cells in NBL patients prior and during current treatment protocols and highlight how these findings are related to clinical outcome. In addition, we discuss potential targets to improve immunogenicity and strategies that may help to improve therapy efficacy. We conclude that immune monitoring during therapy of NBL patients is essential to identify predictive biomarkers to guide patients towards effective treatment, with limited toxicities and optimal quality of life.

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