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1.
Front Immunol ; 13: 911260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967388

RESUMO

Medulloblastoma, a common pediatric malignant tumor, has been recognized to have four molecular subgroups [wingless (WNT), sonic hedgehog (SHH), group 3, group 4], which are defined by the characteristic gene transcriptomic and DNA methylomic profiles, and has distinct clinical features within each subgroup. The tumor immune microenvironment is integral in tumor initiation and progression and might be associated with therapeutic responses. However, to date, the immune infiltrative landscape of medulloblastoma has not yet been elucidated. Thus, we proposed MethylCIBERSORT to estimate the degree of immune cell infiltration and weighted correlation network analysis (WGCNA) to find modules of highly correlated genes. Synthesizing the hub genes in the protein-protein interaction (PPI) network and modules of the co-expression network, we identify three candidate biomarkers [GRB2-associated-binding protein 1 (GAB1), Abelson 1 (ABL1), and CXC motif chemokine receptor type 4 (CXCR4)] via the molecular profiles of medulloblastoma. Given this, we investigated the correlation between these three immune hub genes and immune checkpoint blockade response and the potential of drug prediction further. In addition, this study demonstrated a higher presence of endothelial cells and infiltrating immune cells in Group 3 tumor bulk. The above results will be conducive to better comprehending the immune-related pathogenesis and treatment of medulloblastoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Neoplasias Cerebelares , Meduloblastoma , Proteínas Proto-Oncogênicas c-abl , Receptores CXCR4 , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Biomarcadores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Criança , Células Endoteliais/imunologia , Proteínas Hedgehog/imunologia , Humanos , Meduloblastoma/genética , Meduloblastoma/imunologia , Meduloblastoma/patologia , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/imunologia , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Front Immunol ; 13: 953849, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35990652

RESUMO

Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient's immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
3.
Contrast Media Mol Imaging ; 2022: 7727539, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800227

RESUMO

This article analyzes the relationship between cell division cycle (CDC20) molecules and oncology outcomes in patients with renal clear cell carcinoma (KIRC). CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cycle. The RNA sequencing data and corresponding clinical information of CDC20 molecules were obtained from The Cancer Genome Atlas (TCGA) database. The expression of CDC20 in kidney renal clear cell carcinoma tissue and adjacent normal tissue was detected by immunohistochemical methods. Logistic analysis was performed to analyze the role of CDC20 in the clinicopathological characteristics and prognosis of KIRC. Gene Set Enrichment Analysis (GSEA) was used to identify the signal pathways which were related to CDC20. Independent prognostic factors were evaluated using univariate and multivariate Cox regression analysis. A nomogram involved in CDC20 expression and clinicopathological variables was conducted to predict overall survival (OS) in KIRC patients at 1, 3, and 5 years. Furthermore, the relation between CDC20 and immunity was also studied. Our results showed that CDC20 was upregulated in kidney renal clear cell carcinoma tissues, accompanying shorter OS (all P < 0.05). According to the results obtained by immunohistochemistry and TCGA database, CDC20 was significantly upregulated in kidney renal clear cell carcinoma tissues compared with neighboring normal kidney tissues. Univariate and multivariate Cox regression analysis showed that high expression of CDC20 was an independent prognostic factor of poor prognosis in kidney renal clear cell carcinoma patients (all P < 0.05). GSEA analysis suggested that the high expression of CDC20 was related to eight multiple signaling pathways. In addition, CDC20 was linked to tumour mutation burden (TMB), immune checkpoint molecules, tumour microenvironment, and immunological infiltration.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Proteínas Cdc20/genética , Proteínas Cdc20/imunologia , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Prognóstico , Microambiente Tumoral/imunologia
4.
Sci Rep ; 12(1): 11181, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35778451

RESUMO

Tumor immune microenvironment exerts a profound effect on the population of infiltrating immune cells. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is frequently overexpressed in a variety of cells, particularly during inflammation and tissue injury. However, its function in cancer and immunity remains enigmatic. In this study, we find that TIMP1 is substantially up-regulated during tumorigenesis through analyzing cancer bioinformatics databases, which is further confirmed by IHC tissue microarrays of clinical samples. The TIMP1 level is significantly increased in lymphocytes infiltrating the tumors and correlated with cancer progression, particularly in GBM. Notably, we find that the transcriptional factor Sp1 binds to the promoter of TIMP1 and triggers its expression in GBM. Together, our findings suggest that the Sp1-TIMP1 axis can be a potent biomarker for evaluating immune cell infiltration at the tumor sites and therefore, the malignant progression of GBM.


Assuntos
Glioblastoma , Linfócitos do Interstício Tumoral , Fator de Transcrição Sp1 , Inibidor Tecidual de Metaloproteinase-1 , Carcinogênese , Linhagem Celular Tumoral , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/imunologia , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/imunologia , Microambiente Tumoral/imunologia
5.
Oncoimmunology ; 11(1): 2096362, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800156

RESUMO

The improved survival rate of ovarian cancer (OC) is related to the action of infiltrating cytotoxic T lymphocytes (CTLs). Recently, oncolytic adenoviruses (OAds) have emerged as a key player in treating solid tumors; however, the immunosuppressive tumor microenvironment (TME) and the body-mediated antiviral immune response limit their therapeutic effect. In this study, we tested the hypothesis that bispecific T-cell engagers (BiTEs) could activate and redirect CTLs to increase the anti-tumor effect of OAds. We modified the parental OAd to express a MUC16-targeting BiTE antibody (OAd-MUC16-BiTE), which retained its oncolytic properties and replication ability in vitro. This BiTE secreted from infected tumor cells into the microenvironment binds to MUC16 on target cells and cross-links them to CD3 on T cells, leading to activation, proliferation, and toxicity of T cells against MUC16+ tumor cells. In cell coculture assays, OAd-MUC16-BiTE-mediated oncolysis enhanced T-cell-mediated tumor cell killing and bystander effect. In ex vivo tumor cultures freshly derived from OC patients, OAd-MUC16-BiTE overcame the suppressed immune TME, achieving stronger toxicity than the parental virus. Moreover, in the cell-derived xenograft and patient-derived xenograft model, OAd-MUC16-BiTE showed stronger antitumor activity and increased the number of CTLs, compared with the parental virus. Further, we demonstrated that the OAd-MUC16-BiTE-mediated anti-tumor activity is related to the reversal of the TME and improved MHC I antigen presentation. Overall, our results show how arming OAds with BiTE can overcome limitations in oncolytic virotherapy, yielding a potent therapy that is ready for clinical assessment.


Assuntos
Vírus Oncolíticos , Neoplasias Ovarianas , Adenoviridae/genética , Antígeno Ca-125/metabolismo , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade , Proteínas de Membrana/metabolismo , Terapia Viral Oncolítica , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Microambiente Tumoral/imunologia
6.
J Interferon Cytokine Res ; 42(7): 316-328, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35834651

RESUMO

Cytokines are powerful mediators of immune responses and some, such as interleukin-2 (IL-2), have achieved dramatic responses as cancer immunotherapies. Unfortunately, systemic administration often results in deleterious side effects, prompting exploration of strategies to localize cytokine activity to the tumor microenvironment (TME). To this end, we constructed an IL-2/IL2Ra fusion protein (IL-2FP) with an MMP2/9-specific cleavage site, designed to exploit the dysregulated protease activity in the TME to selectively activate IL-2 in the tumor. To determine if TME protease activity is sufficient to cleave the FP and if FP activity is due to specific cleavage, we created Colon 38 tumor cell lines expressing similar levels of IL-2FPs with either a functional cleavage site [H11(cs-1FP)] or a scrambled, noncleavable sequence [H2(scramFP)]. H11(cs-1FP) tumors demonstrated reduced tumor growth, characterized by regressions not observed in H2(scramFP) tumors. Analysis through qRT-PCR, flow cytometry, and immunohistochemistry indicate robust CD8 responses in the H11(cs-1FP) tumors. Interferon gamma (IFNg) knockout mice revealed that the immune effects of the cleavable FP are mediated through both IFNg-dependent and IFNg-independent mechanisms. Collectively, these data suggest that matrix metalloproteinases (MMPs) in the TME can cleave the IL-2FP specifically, thus enhancing an antitumor response, and provide a rationale for further developing this approach.


Assuntos
Linhagem Celular Tumoral , Imunidade , Interferon gama , Interleucina-2 , Proteínas Recombinantes de Fusão , Microambiente Tumoral , Animais , Linhagem Celular Tumoral/imunologia , Imunidade/imunologia , Interferon gama/imunologia , Interleucina-2/imunologia , Interleucina-2/farmacologia , Camundongos , Peptídeo Hidrolases/imunologia , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/farmacologia , Microambiente Tumoral/imunologia
7.
Front Immunol ; 13: 877896, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720373

RESUMO

The six transcriptomic immune subtypes (ISs) (C1 - C6) were reported to have complex and different interplay between TME and cancer cells in TCGA (The Cancer Genome Atlas) pan-cancer cohort. Our study specifically explored how the consequence of interplay determines the prognosis and the response to therapy in LUAD cohorts. Clinical and molecular information of LUAD patients were from TCGA and Gene Expression Omnibus (GEO). The immune cell populations and gene/pathway enrichment analysis were performed to explore the molecular differences among the C3 IS and other ISs in the LUAD population. The proportion of C3 inflammatory IS was identified as the most common IS in both TCGA (N = 457) and GEO (N = 901) cohorts. The C3 IS was also found to be the most accurate prognostic subtype, which was associated with significantly longer OS (p <0.001) and DFS (p <0.001). The C3 IS presented higher levels of CD8 T, M1 macrophage, and myeloid dendritic cells, while lower levels of M2 macrophages and cancer-associated fibroblast cells. Moreover, the C3 subtype was enriched in the antigen process and presenting, interferon-gamma response, T cell receptor signaling, and natural killer cell-mediated cytotoxicity pathways than C1/C2. In contrast, the C1/C2 presented greater activation of pathways related to the cell cycles, DNA repair, and p53 signaling pathways. The immune-related C3 IS had a great ability to stratify the prognosis of LUAD, providing clues for further pathogenic research. This classification might help direct precision medicine screenings of LUAD patients, thus possibly improving their prognoses.


Assuntos
Adenocarcinoma de Pulmão , Macrófagos , Microambiente Tumoral , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/terapia , Humanos , Interferon gama/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Macrófagos/imunologia , Prognóstico , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
8.
Aging (Albany NY) ; 14(12): 5195-5210, 2022 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-35748773

RESUMO

POC1 centriolar protein A (POC1A) effect in pan-cancer remains uncertain. The POC1A expression in normal and tumor tissues underwent analysis in this study utilizing data from the Genotype-Tissue Expression (GTEx) project and the Cancer Genome Atlas (TCGA) database. POC1A prognostic value and clinicopathological features were assessed utilizing the TCGA cohort. The relationship between immunological cell infiltration and POC1A of TCGA samples downloaded from TIMER2 and ImmuCellAI databases were observed. The relation between POC1A and immunological checkpoints genes, microsatellite instability (MSI) as well as tumor mutation burden (TMB) was also evaluated. Additionally, gene set enrichment analysis (GSEA) was utilized for exploring POC1A potential molecular mechanism in pan-cancer. In almost all 33 tumors, POCA1 showed a high expression. In most cases, high POC1A expression was linked significantly with a poor prognosis. Additionally, Tumor immune infiltration and tumors microenvironment were correlated with the expression of POC1A. In addition, TMB and MSI, as well as immune checkpoint genes in pan-cancer, were related to POC1A expression. In GSEA analysis, POC1A is implicated in cell cycle and immune-related pathways. These results might elucidate the crucial roles of POC1A in pan-cancer as a prognostic biomarker and immunotherapy target.


Assuntos
Proteínas de Ciclo Celular , Proteínas do Citoesqueleto , Neoplasias , Biomarcadores Tumorais/imunologia , Proteínas de Ciclo Celular/imunologia , Proteínas do Citoesqueleto/imunologia , Humanos , Tolerância Imunológica , Instabilidade de Microssatélites , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Microambiente Tumoral/imunologia
9.
Clin Cancer Res ; 28(15): 3182-3184, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35648093

RESUMO

4-1BB has been considered a promising target in cancer immunotherapy for decades. Nevertheless, early 4-1BB-targeted agents demonstrated significant liver immuno-toxicity. A new wave of 4-1BB-based therapy is being developed to circumvent hepatotoxicity with a bispecific molecule that directs 4-1BB agonism to the tumor microenvironment by targeting tumor-associated immune checkpoint molecule PD-L1. See related article by Peper-Gabriel et al., p. 3387.


Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Fatores Imunológicos , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
10.
J Pathol Clin Res ; 8(5): 458-469, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35762092

RESUMO

Programmed cell death-1 (PD-1) and its ligand (PD-L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD-1/PD-L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd-RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT-treated LAd-RC cases were performed. Membranous tumoral PD-L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD-L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD-L1+ immune cells, which frequently exhibited coexpression of PD-1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear ß-catenin+ tumor budding cancer stem cell (CSC)-like features, and unfavorable prognosis. In the LAd-RC cases, stromal CD8+ (but not PD-L1+) immune cell infiltration in pretreatment-biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD-L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD-L1+ and tumoral nuclear ß-catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD-L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD-L1+ immune cells and nuclear ß-catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd-RC, through formation of niche-like lesions that exhibit immune resistance and CSC properties.


Assuntos
Antígeno B7-H1 , Resistencia a Medicamentos Antineoplásicos , Receptor de Morte Celular Programada 1 , Tolerância a Radiação , Neoplasias Retais , beta Catenina , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Núcleo Celular/genética , Núcleo Celular/imunologia , Quimiorradioterapia Adjuvante , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Terapia Neoadjuvante , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Tolerância a Radiação/genética , Tolerância a Radiação/imunologia , Neoplasias Retais/genética , Neoplasias Retais/imunologia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , beta Catenina/genética , beta Catenina/imunologia
11.
Cancer Discov ; 12(8): 1960-1983, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35723626

RESUMO

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. SIGNIFICANCE: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Interleucina-27 , Neoplasias Hepáticas , Linfócitos T Citotóxicos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Interleucina-27/imunologia , Interleucinas/imunologia , Neoplasias Hepáticas/imunologia , Prognóstico , Receptores de Interleucina/imunologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia
12.
Cancer Immunol Res ; 10(7): 787, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35670711

RESUMO

Lack of insight into the immunosuppressive microenvironment of glioblastoma (GBM) hinders successful application of immunotherapy. In this issue, Alanio and colleagues identify a distinct T-cell localization profile between recurrent and de novo GBM highlighting the importance of spatial heterogeneity and providing new avenues to explore to improve GBM outcome. See related article by Alanio et al., p. 800 (3).


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Humanos , Imunoterapia , Linfócitos T/patologia , Microambiente Tumoral/imunologia
13.
Biomed Pharmacother ; 151: 113114, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35594704

RESUMO

Radiation therapy offers limited clinical benefits for patients with pancreatic cancer, partly as a result of the predominantly immunosuppressive microenvironment characteristic of this specific type of cancer. A large number of abnormal blood vessels and high-density fibrous matrices in pancreatic cancer will lead to hypoxia within tumor tissue and hinder immune cell infiltration. We used low-dose X-ray irradiation, also known as low-dose radiation therapy (LDRT), to normalize the blood vessels in pancreatic cancer, while simultaneously administering an inhibitor of focal adhesion kinase (FAK) to reduce pancreatic cancer fibrosis. We found that this treatment successfully reduced pancreatic cancer hypoxia, increased immune cell infiltration, and increased sensitivity to radiation therapy for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Microambiente Tumoral , Terapia por Raios X , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/radioterapia , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Proteína-Tirosina Quinases de Adesão Focal/uso terapêutico , Humanos , Hipóxia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/radioterapia , Microambiente Tumoral/imunologia , Terapia por Raios X/métodos
14.
Front Immunol ; 13: 795164, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634281

RESUMO

Chimeric antigen receptor T-cells (CAR-Ts) are known as revolutionary living drugs that have turned the tables of conventional cancer treatments in certain hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) by achieving US Food and Drug Administration (FDA) approval based on their successful clinical outcomes. However, this type of therapy has not seen the light of victory in the fight against solid tumors because of various restricting caveats including heterogeneous tumor antigen expression and the immunosuppressive tumor microenvironments (TME) that negatively affect the tumor-site accessibility, infiltration, stimulation, activation, and persistence of CAR-Ts. In this review, we explore strategic twists including boosting vaccines and designing implementations that can support CAR-T expansion, proliferation, and tumoricidal capacity. We also step further by underscoring novel strategies for triggering endogenous antitumor responses and overcoming the limitation of poor CAR-T tumor-tissue infiltration and the lack of definitive tumor-specific antigens. Ultimately, we highlight how these approaches can address the mentioned arduous hurdles.


Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias , Humanos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T , Microambiente Tumoral/imunologia
15.
Sci Rep ; 12(1): 8098, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35577913

RESUMO

Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) are established prognostic and predictive biomarkers for certain breast cancer subsets. However, their association with the immune response complexity is not fully understood. Therefore, we analyzed the association between the immune cell fractions in breast cancer tissues and histologically assessed TIL (hTIL) and PD-L1 (hPD-L1). Forty-five tumor and eighteen blood samples were collected from patients with breast cancer. Total leukocyte counts, frequency of 11 immune cell populations, and PD-L1 expression in each cell fraction were evaluated by flow cytometry. TILs and PD-L1 were assessed by hematoxylin and eosin staining and immunohistochemistry, respectively. A higher hTIL score showed association with increased leukocyte infiltration, higher CD4+ and CD8+ T cell proportions, and lower natural killer and natural killer T cell proportions. PD-L1 was highly expressed in nonclassical monocytes, monocyte/macrophages, myeloid-derived suppressor cells, myeloid dendritic cells, dendritic cells, and other lineages in tumors. hPD-L1 positivity reflected PD-L1 expression accurately in these fractions, as well as increased leukocyte infiltration in tumors. These results indicate that hTILs reflect differences in the immune responses in the tumor microenvironment, and certain immune cell fractions are favorably expressed in the PD-L1 pathway in breast cancer microenvironments.


Assuntos
Antígeno B7-H1 , Neoplasias da Mama , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Antígeno B7-H1/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos , Feminino , Humanos , Prognóstico , Microambiente Tumoral/imunologia
16.
Oncoimmunology ; 11(1): 2059874, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35402080

RESUMO

Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Microambiente Tumoral , Antígeno B7-H1/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Microambiente Tumoral/imunologia
17.
Cancer Res ; 82(8): 1464-1466, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35425965

RESUMO

Dietary interventions including alterations in the amount or type of specific macronutrients have been shown to mediate antineoplastic effects in preclinical tumor models, but the underlying mechanisms are only partially understood. In this issue of Cancer Research, Wei and colleagues demonstrate that restoring ketogenesis in the colorectal cancer microenvironment decreases the KLF5-dependent synthesis of CXCL12 by cancer-associated fibroblasts, ultimately enhancing tumor infiltration by immune effector cells and increasing the therapeutic efficacy of an immune checkpoint inhibitor specific for PD-1. These findings provide a novel, therapeutically actionable link between suppressed ketogenesis and immunoevasion in the colorectal cancer microenvironment. See related article by Wei et al., p. 1575.


Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Cetose , Fibroblastos Associados a Câncer/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Microambiente Tumoral/imunologia
18.
Dis Markers ; 2022: 7932655, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401882

RESUMO

Colorectal cancer (COAD) is ranked as the third most common cancer and second in terms of cancer-related deaths worldwide. Due to its poor overall survival and prognosis, the incidents of COAD are significantly increasing. Although treatment methods have greatly been improved in the last decade, it is still not good enough to have satisfactory treatment outcomes. In recent years, immunotherapy has been successful to some extent in the treatment of many cancers but still, many patients do not respond to immunotherapy. Therefore, it is essential to have a deeper understanding of the immune characteristics of the tumor microenvironment and identify meaningful immune targets. In terms of immune targets, COAD has been poorly explored; thus, in the current study, based on the immune cell infiltration score and differentially expressed genes, COAD tumors were classified into hot and cold tumors. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to identify hub genes, construct a prognostic model, and screen potential immune targets. In total, 12 genes (CLK3, CYSLTR2, GJA10, CYP4Z1, FAM185A, LINC00324, EEF1A1P34, EEF1B2P8, PTCSC3, MIR6780A, LINC01666, and RNU6.661P) differentially expressed between hot and cold tumors were screened out. Among them, CYSLTR2 was considered as a potential candidate gene, because it showed a significant positive correlation with immune cell infiltration and immune checkpoints (PDCD1, CD274, and CTLA4). Finally, we constructed and validated a new prognostic model for COAD showing 0.854 AUC for the ROC curve, and these results provide sufficient potential to choose CYSLTR2 as an important immune target for the prognosis of COAD.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Prognóstico , Curva ROC , Microambiente Tumoral/imunologia
19.
Gut Liver ; 16(4): 575-588, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35318288

RESUMO

Background/Aims: This study aimed to explore the effect of gut microbiota-regulated Kupffer cells (KCs) on colorectal cancer (CRC) liver metastasis. Methods: A series of in vivo and in vitro researches were showed to demonstrate the gut microbiota and its possible mechanism in CRC liver metastasis. Results: Fewer liver metastases were identified in the ampicillin-streptomycin-colistin and colistin groups. Increased proportions of Parabacteroides goldsteinii, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides uniformis were observed in the colistin group. The significant expansion of KCs was identified in the ampicillin-streptomycin-colistin and colistin groups. B. vulgatus levels were positively correlated with KC levels. More liver metastases were observed in the vancomycin group. An increased abundance of Parabacteroides distasonis and Proteus mirabilis and an obvious reduction of KCs were noted in the vancomycin group. P. mirabilis levels were negatively related to KC levels. The number of liver metastatic nodules was increased in the P. mirabilis group and decreased in the B. vulgatus group. The number of KCs decreased in the P. mirabilis group and increased in the B. vulgatus group. In vitro, as P. mirabilis or B. vulgatus doses increased, there was an opposite effect on KC proliferation in dose- and time-dependent manners. P. mirabilis induced CT26 cell migration by controlling KC proliferation, whereas B. vulgatus prevented this migration. Conclusions: An increased abundance of P. mirabilis and decreased amount of B. vulgatus play key roles in CRC liver metastasis, which might be related to KC reductions in the liver.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Neoplasias Hepáticas , Fígado , Microambiente Tumoral , Ampicilina , Colistina , Neoplasias Colorretais/patologia , Humanos , Fígado/imunologia , Neoplasias Hepáticas/secundário , Estreptomicina , Microambiente Tumoral/imunologia , Vancomicina
20.
Cancer Res ; 82(5): 766-768, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35247898

RESUMO

While T cells are established major players in antitumor immunity, tumor-associated B cells and antibodies have recently emerged as critical components in modulating immunity in the tumor microenvironment. In the current issue of Cancer Research, Mandal and colleagues show that tumor-infiltrating B cells are associated with improved outcomes in endometrial cancers. Mechanistically, the investigators demonstrate that the immune response is mediated by class-switched IgA binding to the polymeric immunoglobulin receptor in tumor cells, resulting in tumor cell-intrinsic activation of inflammatory pathways. These findings highlight that coordinated B-cell and T-cell responses may predict improved outcomes in patients with endometrial cancer and set the groundwork to further investigate the mechanisms by which humoral immunity could be exploited for cancer immunotherapy. See related article by Mandal et al., p. 859.


Assuntos
Neoplasias do Endométrio , Linfócitos T , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Imunoterapia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
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