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1.
Elife ; 122024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829686

RESUMO

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.


Over time cancer patients can become resistant to traditional treatments such as chemotherapy and radiotherapy. In some cases, this can be counteracted by administering a new type of treatment called immune checkpoint inhibition which harnesses a patient's own immune system to eradicate the tumor. However, a significant proportion of cancers remain resistant, even when these immunotherapy drugs are used. This is potentially caused by tumors reactivating a gene called DUX4, which is briefly turned on in the early embryo shortly after fertilization, but suppressed in healthy adults. Activation of DUX4 during the early stages of cancer has been shown to remove the cell surface proteins the immune system uses to recognize tumors. However, it remained unclear whether DUX4 changes the response to immunotherapy in more advanced cancers which have begun to spread and metastasize to other parts of the body. To investigate, Pineda and Bradley analyzed publicly available sequencing data which revealed the genes turned on and off in patients with different types of cancer. The analysis showed that DUX4 is reactivated in approximately 10­50% of advanced bladder, breast, kidney, prostate and skin cancers. Next, Pineda and Bradley studied a cohort of patients with advanced bladder cancer who had been treated with immune checkpoint inhibitors. They found that patients with tumors in which DUX4 had been turned back on had shorter survival times than patients who had not reactivated the gene. These results suggest that the activity of DUX4 could be used to predict which patients with advanced bladder cancer may benefit from immune checkpoint inhibitors. In the future, this work could be extended to see if DUX4 could be used as a prognostic tool for other types of cancer. Future studies could also investigate if the DUX4 gene could be a therapeutic target for mitigating resistance to immunotherapy in metastatic cancers.


Assuntos
Proteínas de Homeodomínio , Evasão da Resposta Imune , Imunoterapia , Neoplasias , Humanos , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Imunoterapia/métodos , Neoplasias/terapia , Neoplasias/imunologia , Masculino , Feminino , Metástase Neoplásica , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Regulação Neoplásica da Expressão Gênica
2.
J Exp Med ; 221(8)2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38842526

RESUMO

The first descriptions of "non-specific" killing of tumor cells by lymphocytes were reported in 1973, and subsequently, the mediators of the activity were named "natural killer" (NK) cells by Rolf Kiessling and colleagues at the Karolinska Institute in 1975. The activity was detected in mice, rats, and humans that had no prior exposure to the tumors, major histocompatibility complex (MHC) antigen matching of the effectors and tumor cells was not required, and the cells responsible were distinct from MHC-restricted, antigen-specific T cells. In the ensuing five decades, research by many labs has extended knowledge of NK cells beyond an in vitro curiosity to demonstrate their in vivo relevance in host defense against tumors and microbial pathogens and their role in regulation of the immune system. This brief Perspective highlights a timeline of a few selected advancements in NK cell biology from a personal perspective of being involved in this quest.


Assuntos
Células Matadoras Naturais , Células Matadoras Naturais/imunologia , Animais , Humanos , História do Século XX , Camundongos , História do Século XXI , Neoplasias/imunologia , Ratos
3.
Technol Cancer Res Treat ; 23: 15330338241260658, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38847740

RESUMO

Objective: DNA methylation is an essential epigenetic marker governed by DNA methyltransferases (DNMTs), which can influence cancer onset and progression. However, few studies have provided an integrated analysis of the relevance of DNMT family genes to cell stemness, the tumor microenvironment (TME), and immunotherapy biomarkers across diverse cancers. Methods: This study investigated the impact of five DNMTs on transcriptional profiles, prognosis, and their association with Ki67 expression, epithelial-mesenchymal transition signatures, stemness scores, the TME, and immunological markers across 31 cancer types from recognized public databases. Results: The results indicated that DNMT1/DNMT3B/DNMT3A expression increased, whereas TRDMT1/DNMT3L expression decreased in most cancer types. DNMT family genes were identified as prognostic risk factors for numerous cancers, as well as being prominently associated with immune, stromal, and ESTIMATE scores, as well as with immune-infiltrating cell levels. Expression of the well-known immune checkpoints, PDCD1 and CILA4, was noticeably related to DNMT1/DNMT3A/DNMT3B expression. Finally, we validated the role of DNMT1 in MCF-7 and HepG2-C3A cell lines through its knockdown, whereafter a decrease in cell proliferation and migration ability in vitro was observed. Conclusion: Our study comprehensively expounded that DNMT family genes not only behave as promising prognostic factors but also have the potential to serve as therapeutic targets in cancer immunotherapy for various types of cancer.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Prognóstico , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Epigênese Genética , Perfilação da Expressão Gênica , Proliferação de Células , Biologia Computacional/métodos , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo
4.
Sci Rep ; 14(1): 13133, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849432

RESUMO

The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer. Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56highCD16+), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG). Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D. Strikingly, a NKG2C+CD57-FcεRIγ+ NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients' bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.


Assuntos
Proliferação de Células , Células Matadoras Naturais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Vacina BCG/imunologia , Vacina BCG/administração & dosagem , Mycobacterium bovis/imunologia , Ativação Linfocitária/efeitos dos fármacos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Interleucinas/metabolismo , Antígeno CD56/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo
5.
J Exp Clin Cancer Res ; 43(1): 155, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822401

RESUMO

Longitudinal sampling of tumor tissue from patients with solid cancers, aside from melanoma and a few other cases, is often unfeasible, and thus may not capture the plasticity of interactions between the tumor and immune system under selective pressure of a given therapy. Peripheral blood analyses provide salient information about the human peripheral immunome while offering technical and practical advantages over traditional tumor biopsies, and should be utilized where possible alongside interrogation of the tumor. Some common blood-based biomarkers used to study the immune response include immune cell subsets, circulating tumor DNA, and protein analytes such as cytokines. With the recent explosion of immune checkpoint inhibitors (ICI) as a modality of treatment in multiple cancer types, soluble immune checkpoints have become a relevant area of investigation for peripheral immune-based biomarkers. However, the exact functions of soluble immune checkpoints and their roles in cancer for the most part remain unclear. This review discusses current literature on the production, function, and expression of nine soluble immune checkpoints - sPD-L1, sPD-1, sCTLA4, sCD80, sTIM3, sLAG3, sB7-H3, sBTLA, and sHVEM - in patients with solid tumors, and explores their role as biomarkers of response to ICI as well as to conventional therapies (chemotherapy, radiotherapy, targeted therapy, and surgery) in cancer patients.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Proteínas de Checkpoint Imunológico/metabolismo , Biomarcadores Tumorais , Imunoterapia/métodos
6.
Mol Cancer ; 23(1): 117, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824567

RESUMO

Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.


Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/métodos , Microambiente Tumoral/imunologia , Animais , Imunoterapia/métodos
7.
Int J Nanomedicine ; 19: 4803-4834, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38828205

RESUMO

The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/PD-L1 inhibition therapy, encouraging further investigation into this promising field.


Assuntos
Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Neoplasias , Receptor de Morte Celular Programada 1 , RNA Circular , RNA Interferente Pequeno , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inibidores , RNA Interferente Pequeno/genética , RNA Circular/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/genética , Imunoterapia/métodos , Animais , RNA de Interação com Piwi
8.
J Nanobiotechnology ; 22(1): 308, 2024 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-38825711

RESUMO

Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS.


Assuntos
Adjuvantes Imunológicos , Vacinas Anticâncer , Nanotecnologia , Neoplasias , Vacinas de mRNA , Humanos , Vacinas Anticâncer/imunologia , Nanotecnologia/métodos , Neoplasias/terapia , Neoplasias/imunologia , Animais , Sistemas de Liberação de Medicamentos/métodos , COVID-19/prevenção & controle , Adjuvantes de Vacinas , RNA Mensageiro/genética , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia
9.
Nat Immunol ; 25(6): 1020-1032, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831106

RESUMO

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Receptores Imunológicos , Membro 14 de Receptores do Fator de Necrose Tumoral , Microambiente Tumoral , Animais , Humanos , Imunoterapia Adotiva/métodos , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/imunologia , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Camundongos , Microambiente Tumoral/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Linfócitos T Reguladores/imunologia , Transdução de Sinais , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/terapia , Camundongos Knockout
10.
J Cell Mol Med ; 28(11): e18362, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837666

RESUMO

Chimeric antigen receptor- (CAR-)modified T cells have been successfully used to treat blood cancer. With the improved research on anti-tumour adoptive cell therapy, researchers have focused on immune cells other than T lymphocytes. Natural killer (NK) cells have received widespread attention as barriers to natural immunity. Compared to T lymphocyte-related adoptive cell therapy, the use of NK cells to treat tumours does not cause graft-versus-host disease, significantly improving immunity. Moreover, NK cells have more sources than T cells, and the related modified cells are less expensive. NK cells function through several pathways in anti-tumour mechanisms. Currently, many anti-tumour clinical trials have used NK cell-related adoptive cell therapies. In this review, we have summarized the recent progress in NK cell-related adoptive cellular immunotherapy for tumour treatment and propose the current challenges faced by CAR-NK cell therapy.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais
11.
J Transl Med ; 22(1): 532, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831284

RESUMO

BACKGROUND: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. METHODS: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). RESULTS: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. CONCLUSIONS: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.


Assuntos
Sinergismo Farmacológico , Inibidores de Checkpoint Imunológico , Espécies Reativas de Oxigênio , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linhagem Celular Tumoral , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/imunologia , Camundongos Endogâmicos C57BL , Feminino , Morte Celular/efeitos dos fármacos
13.
Cancer Immunol Immunother ; 73(8): 150, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38832948

RESUMO

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Mutação , Neoplasias , Receptores de Antígenos de Linfócitos T , Humanos , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/genética , Imunoterapia/métodos , Antígeno HLA-A11/genética , Antígeno HLA-A11/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral
14.
Cancer Immunol Immunother ; 73(8): 137, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833034

RESUMO

Tumor-infiltrating lymphocyte (TIL) deficiency is the most conspicuous obstacle to limit the cancer immunotherapy. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have achieved great success in clinical practice. However, due to the limitation of response rates of ICIs, some patients fail to benefit from monotherapy. Thus, novel combination therapy that could improve the response rates emerges as new strategies for cancer treatment. Here, we reported that the natural product rocaglamide (RocA) increased tumor-infiltrating T cells and promoted Th17 differentiation of CD4+ TILs. Despite RocA monotherapy upregulated PD-1 expression of TILs, which was considered as the consequence of T cell activation, combining RocA with anti-PD-1 antibody significantly downregulated the expression of PD-1 and promoted proliferation of TILs. Taken together, these findings demonstrated that RocA could fuel the T cell anti-tumor immunity and revealed the remarkable potential of RocA as a therapeutic candidate when combining with the ICIs.


Assuntos
Benzofuranos , Diferenciação Celular , Inibidores de Checkpoint Imunológico , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1 , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Animais , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Diferenciação Celular/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Feminino , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linhagem Celular Tumoral
15.
Cancer Immunol Immunother ; 73(8): 138, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833177

RESUMO

Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.


Assuntos
Inibidores de Checkpoint Imunológico , Interleucinas , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Interleucinas/metabolismo , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Humanos , Microambiente Tumoral/imunologia , Terapia Combinada , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Feminino , Neoplasias/imunologia , Neoplasias/terapia , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral
16.
Cancer Immunol Immunother ; 73(8): 155, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834888

RESUMO

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.


Assuntos
Antígeno B7-H1 , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Front Immunol ; 15: 1394593, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38835776

RESUMO

Background: Microsatellite instability (MSI) secondary to mismatch repair (MMR) deficiency is characterized by insertions and deletions (indels) in short DNA sequences across the genome. These indels can generate neoantigens, which are ideal targets for precision immune interception. However, current neoantigen databases lack information on neoantigens arising from coding microsatellites. To address this gap, we introduce The MicrOsatellite Neoantigen Discovery Tool (MONET). Method: MONET identifies potential mutated tumor-specific neoantigens (neoAgs) by predicting frameshift mutations in coding microsatellite sequences of the human genome. Then MONET annotates these neoAgs with key features such as binding affinity, stability, expression, frequency, and potential pathogenicity using established algorithms, tools, and public databases. A user-friendly web interface (https://monet.mdanderson.org/) facilitates access to these predictions. Results: MONET predicts over 4 million and 15 million Class I and Class II potential frameshift neoAgs, respectively. Compared to existing databases, MONET demonstrates superior coverage (>85% vs. <25%) using a set of experimentally validated neoAgs. Conclusion: MONET is a freely available, user-friendly web tool that leverages publicly available resources to identify neoAgs derived from microsatellite loci. This systems biology approach empowers researchers in the field of precision immune interception.


Assuntos
Antígenos de Neoplasias , Bases de Dados Genéticas , Repetições de Microssatélites , Humanos , Repetições de Microssatélites/genética , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Instabilidade de Microssatélites , Mutação da Fase de Leitura , Software , Biologia Computacional/métodos , Neoplasias/genética , Neoplasias/imunologia
18.
Front Immunol ; 15: 1389194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840905

RESUMO

Past research has identified that cancer cells sustain several cancer hallmarks by impairing function of the endolysosomal system (ES). Thus, maintaining the functional integrity of endolysosomes is crucial, which heavily relies on two key protein families: soluble hydrolases and endolysosomal membrane proteins. Particularly members of the TPC (two-pore channel) and TRPML (transient receptor potential mucolipins) families have emerged as essential regulators of ES function as a potential target in cancer therapy. Targeting TPCs and TRPMLs has demonstrated significant impact on multiple cancer hallmarks, including proliferation, growth, migration, and angiogenesis both in vitro and in vivo. Notably, endosomes and lysosomes also actively participate in various immune regulatory mechanisms, such as phagocytosis, antigen presentation, and the release of proinflammatory mediators. Yet, knowledge about the role of TPCs and TRPMLs in immunity is scarce. This prompts a discussion regarding the potential role of endolysosomal ion channels in aiding cancers to evade immune surveillance and destruction. Specifically, understanding the interplay between endolysosomal ion channels and cancer immunity becomes crucial. Our review aims to comprehensively explore the current knowledge surrounding the roles of TPCs and TRPMLs in immunity, whilst emphasizing the critical need to elucidate their specific contributions to cancer immunity by pointing out current research gaps that should be addressed.


Assuntos
Canais de Cálcio , Endossomos , Lisossomos , Neoplasias , Canais de Potencial de Receptor Transitório , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Lisossomos/metabolismo , Lisossomos/imunologia , Endossomos/metabolismo , Endossomos/imunologia , Animais , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Cálcio/metabolismo , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/imunologia , Canais de Dois Poros
19.
Front Immunol ; 15: 1388176, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840908

RESUMO

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.


Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/patologia , Animais , Imunidade Inata , Comunicação Celular/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Evasão Tumoral , Imunoterapia/métodos
20.
Front Immunol ; 15: 1395714, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840921

RESUMO

Vascular cell adhesion is a complex orchestration of events that commonly feature lectin-ligand interactions between circulating cells, such as immune, stem, and tumor cells, and endothelial cells (ECs) lining post-capillary venules. Characteristically, circulating cell adherence to the vasculature endothelium is initiated through interactions between surface sialo-fucosylated glycoprotein ligands and lectins, specifically platelet (P)- or endothelial (E)-selectin on ECs or between leukocyte (L)-selectin on circulating leukocytes and L-selectin ligands on ECs, culminating in circulating cell extravasation. This lectin-ligand interplay enables the migration of immune cells into specific tissue sites to help maintain effective immunosurveillance and inflammation control, the homing of stem cells to bone marrow or tissues in need of repair, and, unfortunately, in some cases, the dissemination of circulating tumor cells (CTCs) to distant metastatic sites. Interestingly, there is a growing body of evidence showing that the family of ß-galactoside-binding lectins, known as galectins, can also play pivotal roles in the adhesion of circulating cells to the vascular endothelium. In this review, we present contemporary knowledge on the significant roles of host- and/or tumor-derived galectin (Gal)-3, -8, and -9 in facilitating the adhesion of circulating cells to the vascular endothelium either directly by acting as bridging molecules or indirectly by triggering signaling pathways to express adhesion molecules on ECs. We also explore strategies for interfering with galectin-mediated adhesion to attenuate inflammation or hinder the metastatic seeding of CTCs, which are often rich in galectins and/or their glycan ligands.


Assuntos
Adesão Celular , Endotélio Vascular , Galectinas , Humanos , Galectinas/metabolismo , Animais , Endotélio Vascular/metabolismo , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/patologia , Células Endoteliais/metabolismo , Neoplasias/patologia , Neoplasias/imunologia , Neoplasias/metabolismo
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