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1.
Anticancer Res ; 41(10): 4895-4905, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593437

RESUMO

BACKGROUND/AIM: The limited efficacy of immune checkpoint inhibitors in colorectal cancer (CRC) is likely due to immunosuppressive mechanisms including T cell exhaustion caused by inhibitory immune checkpoints in the tumor microenvironment. MATERIALS AND METHODS: We investigated the expression status of the inhibitory immune checkpoint receptors on tumor-infiltrating T cells and their ligands on tumor cells by flow cytometry and immunohistochemistry, using surgically-resected specimens of CRC. RESULTS: Flow cytometry analysis indicated that TIM-3, TIGIT, and PD-1 were expressed on tumor-infiltrating CD4+ (8.3%, 56.0%, 26.1%) and CD8+ T cells (8.2%, 51.6%, 23.5%), and CRC cells abundantly expressed PD-L1, CEACAM-1, and CD155 (2.2%, 77.0%, 46.8%). Immunohistochemical analysis revealed that the tumor proportional score of PD-L1, CEACAM-1, and CD155 was 42.4%, 54.2%, and 52.1%, respectively. CONCLUSION: PD-1, TIM-3, and TIGIT axes may reduce T cell function in the CRC tumor microenvironment.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Checkpoint Imunológico/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptores Imunológicos/metabolismo , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Prognóstico
2.
Anticancer Res ; 41(10): 4907-4916, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593438

RESUMO

BACKGROUND: Interleukin-6 receptor antibody (IL6R) inhibits colony formation and invasion by colorectal carcinoma (CRC) in vitro. We examined the effect of IL6R antibody on tumor growth of CRC xenografts in vivo. MATERIALS AND METHODS: SW480 cells inoculated subcutaneously into NU/NU mice were treated with anti-IL6R and tumor histology and growth-related signaling were subsequently estimated by hematoxylin and eosin and immunohistochemical staining. RESULTS: Tumor growth was inhibited by anti-IL6R treatment at dosages of both 0.1 and 1.0 mg/kg. Tumor cells had invaded into surrounding tissues in untreated mice, while there was no invasion of tumors in the IL6R antibody-treated mice. The expression of Ki-67, signal transducer and activator of transcription protein 3 (STAT3) and phosphor-extracellular signal-regulated kinase 1 and 2 (ERK1/2) were suppressed in anti-IL6R-treated tumors. CONCLUSION: IL6R antibody inhibited tumor growth and invasiveness in vivo by suppressing the expression of Ki-67, STAT3 and phosphor-ERK1/2. The results imply that the anti-IL6R may be a promising targeted drug for CRC.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Colorretais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Receptores de Interleucina-6/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Receptores de Interleucina-6/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 41(10): 4857-4865, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593433

RESUMO

BACKGROUND/AIM: M1 macrophages have antitumour effects, while M2 macrophages promote tumour proliferation and invasion. The clinical significance of the M2-specific marker CD204 has not been elucidated in colorectal cancer (CRC). We investigated the prognostic significance of CD204- and CD68-positivity in specimens from patients with CRC and examined the effects of M2 polarized-macrophages on the proliferative and invasive potentials of CRC cell lines in vitro. MATERIALS AND METHODS: Surgical tumour specimens from 206 patients with Stage II and III CRC were examined by immunohistochemistry. Proliferation and invasion assays and flow cytometry were used to investigate CD204 expression in macrophages co-cultured with three CRC cell lines. RESULTS: Infiltration of CD204-positive cells was significantly associated with shorter overall survival and relapse-free survival; no association was observed for CD68. M2-polarized macrophages significantly promoted proliferation and invasion of CRC cells. CONCLUSION: Higher infiltration of CD204-positive macrophages into the tumour-microenvironment might be prognostically important in CRC.


Assuntos
Neoplasias Colorretais/patologia , Receptores Depuradores Classe A/imunologia , Macrófagos Associados a Tumor/imunologia , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Microambiente Tumoral/imunologia
4.
Biomed Res Int ; 2021: 1124985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471634

RESUMO

Objective: Thrombospondin 2 (THBS2) acts as oncogenic or tumor suppressive gene in diverse cancers. Here we studied the prognostic and immunological role of THBS2 in colorectal cancer (CRC) using bioinformatic analysis. Methods: The genetic and protein expression of THBS2 in CRC were explored across several databases, including ONCOMINE, GEPIA2, TIMER 2.0, UALCAN and HPA databases. Correlation between THBS2 expression and clinical features in CRC was assessed using UALCAN tool. Prognostic analysis was performed using GEPIA2 and PrognoScan. Immune infiltration correlation with THBS2 in CRC was investigated with TIMER 2.0 and TISIDB. THBS2 binding and correlated genes were analyzed using String, GEPIA2, and TIMER 2.0. Results: THBS2 was significantly higher in CRC across multiple databases. Age and histological subtype were correlated with THBS2 level. High THBS2 expression correlated with short overall and disease-free survival. THBS2 expression was positively correlated with immune infiltrates in CRC. Moreover, extracellular matrix structural constituent and organization, PI3K-Akt pathway, were involved in the functional mechanisms of THBS2. Conclusions: THBS2 correlates with poor prognosis and immune infiltration in CRC. THBS2 may act as a prognostic and immunological biomarker for CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Linfócitos do Interstício Tumoral/imunologia , Trombospondinas/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Bases de Dados Genéticas , Humanos , Prognóstico , Taxa de Sobrevida , Trombospondinas/imunologia
5.
Nat Commun ; 12(1): 5405, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518538

RESUMO

Tumor cells evade T cell-mediated immunosurveillance via the interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells. Strategies disrupting PD-1/PD-L1 have shown clinical benefits in various cancers. However, the limited response rate prompts us to investigate the molecular regulation of PD-L1. Here, we identify trafficking protein particle complex subunit 4 (TRAPPC4), a major player in vesicular trafficking, as a crucial PD-L1 regulator. TRAPPC4 interacts with PD-L1 in recycling endosomes, acting as a scaffold between PD-L1 and RAB11, and promoting RAB11-mediated recycling of PD-L1, thus replenishing its distribution on the tumor cell surface. TRAPPC4 depletion leads to a significant reduction of PD-L1 expression in vivo and in vitro. This reduction in PD-L1 facilitates T cell-mediated cytotoxicity. Overexpression of Trappc4 sensitizes tumor cells to checkpoint therapy in murine tumor models, suggesting TRAPPC4 as a therapeutic target to enhance anti-tumor immunity.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas de Transporte Vesicular/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Endossomos/imunologia , Endossomos/metabolismo , Células HCT116 , Humanos , Espaço Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Transporte Proteico , Interferência de RNA , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
6.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360996

RESUMO

ß-Casomorphin-7 (BCM) is a degradation product of ß-casein, a milk component, and has been suggested to affect the immune system. However, its effect on mucosal immunity, especially anti-tumor immunity, in cancer-bearing individuals is not clear. We investigated the effects of BCM on lymphocytes using an in vitro system comprising mouse splenocytes, a mouse colorectal carcinogenesis model, and a mouse orthotopic colorectal cancer model. Treatment of mouse splenocytes with BCM in vitro reduced numbers of cluster of differentiation (CD) 20+ B cells, CD4+ T cells, and regulatory T cells (Tregs), and increased CD8+ T cells. Administration of BCM and the CD10 inhibitor thiorphan (TOP) to mice resulted in similar alterations in the lymphocyte subsets in the spleen and intestinal mucosa. BCM was degraded in a concentration- and time-dependent manner by the neutral endopeptidase CD10, and the formed BCM degradation product did not affect the lymphocyte counts. Furthermore, degradation was completely suppressed by TOP. In the azoxymethane mouse colorectal carcinogenesis model, the incidence of aberrant crypt foci, adenoma, and adenocarcinoma was reduced by co-treatment with BCM and TOP. Furthermore, when CT26 mouse colon cancer cells were inoculated into the cecum of syngeneic BALB/c mice and concurrently treated with BCM and TOP, infiltration of CD8+ T cells was promoted, and tumor growth and liver metastasis were suppressed. These results suggest that by suppressing the BCM degradation system, the anti-tumor effect of BCM is enhanced and it can suppress the development and progression of colorectal cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Endorfinas/uso terapêutico , Linfócitos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Endorfinas/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Fragmentos de Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Baço/citologia , Baço/imunologia , Tiorfano/farmacologia
7.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445503

RESUMO

Obesity is a major risk factor for developing cancer, with obesity-induced immune changes and inflammation in breast (BC) and colorectal cancer (CRC) providing a potential link between the two. This study investigates systemic effects of obesity on adaptive and innate immune cells in healthy and tumour-bearing mice. Immune cells from lean and obese mice were phenotyped prior to implantation of either BC (C57mg and EO771.LMB) or CRC (MC38) cells as tumour models. Tumour growth rate, tumour-infiltrating lymphocytes (TIL) and peripheral blood immune cell populations were compared between obese and lean mice. In vitro studies showed that naïve obese mice had higher levels of myeloid cells in the bone marrow and bone marrow-derived dendritic cells expressed lower levels of activation markers compared to cells from their lean counterparts. In the tumour setting, BC tumours grew faster in obese mice than in lean mice and lower numbers of TILs as well as higher frequency of exhausted T cells were observed. Data from peripheral blood showed lower levels of myeloid cells in tumour-bearing obese mice. This study highlights that systemic changes to the immune system are relevant for tumour burden and provides a potential mechanism behind the effects of obesity on cancer development and progression in patients.


Assuntos
Neoplasias da Mama/patologia , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/metabolismo , Obesidade/imunologia , Imunidade Adaptativa , Animais , Neoplasias da Mama/imunologia , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Feminino , Humanos , Masculino , Camundongos , Células Mieloides/metabolismo , Transplante de Neoplasias , Microambiente Tumoral
8.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360782

RESUMO

Colorectal carcinogenesis is the second most common cause of mortality across all types of malignancies, followed by hepatic and stomach cancers. Chemotherapy and radiotherapy are key approaches to treating cancer patients, but these carry major concerns, such as a high risk of side effects, poor accessibility, and the non-selective nature of chemotherapeutics. A number of natural products have been identified as countering various forms of cancer with fewer side effects. The potential impact of vitamins and minerals on long-term health, cognition, healthy development, bone formation, and aging has been supported by experimental and epidemiological studies. Successful treatment may thus be highly influenced by the nutritional status of patients. An insufficient diet could lead to detrimental effects on immune status and tolerance to treatment, affecting the ability of chemotherapy to destroy cancerous cells. In recent decades, most cancer patients have been taking vitamins and minerals to improve standard therapy and/or to decrease the undesirable side effects of the treatment together with the underlying disease. On the other hand, taking dietary supplements during cancer therapy may affect the effectiveness of chemotherapy. Thus, micronutrients in complementary oncology must be selected appropriately and should be taken at the right time. Here, the potential impact of micronutrients on gastro-intestinal and hepatic cancers is explored and their molecular targets are laid down.


Assuntos
Neoplasias Colorretais , Suplementos Nutricionais , Neoplasias Hepáticas , Micronutrientes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Micronutrientes/imunologia , Micronutrientes/uso terapêutico
9.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445193

RESUMO

Colorectal cancer (CRC) is a malignant tumor in the digestive system whose incidence and mortality is high-ranking among tumors worldwide. The initiation and progression of CRC is a complex process involving genetic alterations in cancer cells and multiple factors from the surrounding tumor cell microenvironment. As accumulating evidence has shown, tumor-associated macrophages (TAMs)-as abundant and active infiltrated inflammatory cells in the tumor microenvironment (TME)-play a crucial role in CRC. This review focuses on the different mechanisms of TAM in CRC, including switching of phenotypical subtypes; promoting tumor proliferation, invasion, and migration; facilitating angiogenesis; mediating immunosuppression; regulating metabolism; and interacting with the microbiota. Although controversy remains in clinical evidence regarding the role of TAMs in CRC, clarifying their significance in therapy and the prognosis of CRC may shed new light on the optimization of TAM-centered approaches in clinical care.


Assuntos
Neoplasias Colorretais/patologia , Macrófagos Associados a Tumor/patologia , Animais , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Gerenciamento Clínico , Humanos , Imunoterapia , Invasividade Neoplásica/diagnóstico , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Prognóstico , Macrófagos Associados a Tumor/imunologia
10.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298878

RESUMO

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Animais , Progressão da Doença , Armadilhas Extracelulares/fisiologia , Humanos , Metástase Neoplásica/imunologia
11.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200820

RESUMO

Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.


Assuntos
Reprogramação Celular , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Humanos
12.
Aging (Albany NY) ; 13(13): 17548-17567, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233297

RESUMO

The C-X-C motif (CXC) chemokines are a family of chemotactic molecules that have been identified as potential prognostic markers and prospective therapeutic targets for many kinds of cancer types. Increasing evidence shows that CXC chemokines are associated with the progression of colorectal cancer (CRC); however, the correlations of CXC chemokines with prognostic and immune infiltrates in CRC remain to be clarified. In this study, we analyzed the mRNA expression level, prognostic data and immune infiltrates of CXC chemokines in CRC patients from the Gene Expression Profiling Interactive Analysis, Oncomine, cBioPortal and databases using GeneMANIA, STRING, DAVID 6.8, and TIMER. Our results showed that CXCL1/2/3/4/5/8/9/10/11/13/14/16 were significantly overexpressed in CRC tissues. Furthermore, expression of CXCL1/2/3/9/10/11 was associated with tumor stage in CRC. A significant association was also identified between the co-expression of CXCL16 with EGFR, KRAS and NRAS. In addition, the survival analysis suggested that high CXCL2/3/8/9/10/11/14 expression is correlated with clinical outcomes of CRC patients. Moreover, a significant association was observed between the CXCL8/9/10/11 expression and immune infiltration in colonic and rectal adenocarcinoma. Overall, CXC chemokines are not only implicated as prognostic biomarkers for CRC patients, but may also influence the immune status of CRC tissues.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Quimiocinas CXC/análise , Quimiocinas CXC/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/análise , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , Estudos Prospectivos , Análise de Sobrevida
13.
FASEB J ; 35(8): e21776, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34324740

RESUMO

Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects of CD8+ T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Calnexina/metabolismo , Neoplasias Colorretais/terapia , Antígenos de Histocompatibilidade Classe II/metabolismo , MicroRNAs/metabolismo , Animais , Calnexina/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , MicroRNAs/genética , Neoplasias Experimentais/terapia
14.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206051

RESUMO

Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1-/- mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1-/--tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1-/- mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1ß were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.


Assuntos
Antígeno B7-H1/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Proteína 1 Homóloga a MutL/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Quimiocina CCL4/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/sangue , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Reparo de Erro de Pareamento de DNA/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-13/sangue , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Células Supressoras Mieloides , Síndromes Neoplásicas Hereditárias/sangue , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia , Fator de Necrose Tumoral alfa/sangue
15.
Nat Immunol ; 22(8): 947-957, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239121

RESUMO

One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocina CXCL1/metabolismo , Neoplasias Colorretais/imunologia , Células Supressoras Mieloides/imunologia , Receptor 2 Toll-Like/imunologia , Microambiente Tumoral/imunologia , Alarminas/genética , Alarminas/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
16.
Aging (Albany NY) ; 13(11): 14590-14603, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083496

RESUMO

CD8+ cytotoxic T-lymphocytes are essential components of the anti-tumor immunity. To better understand the expansion of CD8+ T-cells we used multiplex fluorescence immunohistochemistry to study Ki67+CD8+ cells in normal lymphoid tissues, selected inflammatory diseases and cancers in 41 large sections/ microenvironment tissue microarrays (TMAs) as well as 765 samples in a conventional TMA format. The evaluation of more than 20 different compartments of normal lymphoid tissues revealed that the percentage of proliferating (ki67+) CD8+ cells did commonly not exceed 3%. In inflammations, the percentage of Ki67+CD8+ cells was more variable and higher compared to normal tissues. In cancers, the percentage of Ki67+CD8+ cells was higher in the tumor center than at the invasive margin. In the tumor center of 765 colorectal cancers, the density of Ki67+CD8+ cells and the percentage of proliferating CD8+ cytotoxic T-cells was significantly associated with microsatellite instability (p<0.0001), pT (p<0.0002) and pN category (p<0.0098). In summary, these data show that the percentage of Ki67+CD8+ cells is usually at a baseline proliferation rate below 3% in healthy secondary lymphoid organs. This rate is often markedly higher in inflammatory and neoplastic diseases compared to normal tissues. The striking link with unfavorable tumor features in colorectal cancer suggest a potential clinical utility of assessing the percentage of Ki67+CD8+ cells to predict patients outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Inflamação/imunologia , Tecido Linfoide/imunologia , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Antígeno Ki-67/metabolismo , Fenótipo
17.
J Cancer Res Clin Oncol ; 147(9): 2609-2619, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34115241

RESUMO

BACKGROUND: Intra-abdominal infection after curative surgery for colorectal cancer is a serious complication associated with an increased risk of recurrence. Lipopolysaccharides (LPS)-an essential component of the cell wall of Gram-negative bacteria-were found to exert a protumorigenic effect by stimulating the inflammatory pathology and formation of neutrophil extracellular traps (NETs). This study was conducted to test whether LPS-induced formation of NETs promotes the development of cancer and metastasis. METHODS: The clinical characteristics, incidence of relapse, and serum myeloperoxidase-DNA complexes of 40 patients with infection and 40 patients without infection after curative surgery were analyzed. The effects of LPS on the induction of NETs were evaluated in a mouse model of colorectal cancer and liver metastasis. The toll-like receptor 9 (TLR9)-a DNA receptor-was knocked down to assess its effect on the mitogen-activated protein kinase pathway and activities implicated in the formation of NETs. RESULTS: Analysis of the clinical data obtained from these patients showed the significant relation of the formation of NETs and incidence of metastasis and survival rates. Subsequent in vitro experiments revealed an increased level of citrullinated-histone H3 and myeloperoxidase-DNA in LPS-injected mice with colorectal cancer. In the mimic metastatic model, injection of LPS enhanced the metastatic capacity, which was then attenuated by DNase I. This suggested that the formation of NETs was activated by LPS. Injection of TLR9-knockdown HCT116 cells in mice, followed by induction through LPS, mitigated the level of citrullinated-histone H3 and myeloperoxidase-DNA. This finding implied that the formation of NETs was suppressed. CONCLUSION: These findings shed light on the mechanism underlying the relationship between the elevated rate of colorectal cancer recurrence in patients who underwent surgery and the incidence of infection. This mechanism involves the protumorigenic activities of LPS-induced formation of NETs. The NETs which could be mediated by the TLR9 and the mitogen-activated protein kinase signaling pathway.


Assuntos
Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Armadilhas Extracelulares , Lipopolissacarídeos/efeitos adversos , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Idoso , Animais , Apoptose , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Masculino , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Commun Biol ; 4(1): 694, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099861

RESUMO

Tumor-infiltrating lymphocytes (TIL), which include tumor-specific T lymphocytes with frequency, are used for adoptive cell transfer therapy (ACT) in clinical practice. The optimization of TIL preparation has been investigated to reduce the senescence and increase the abundance of TIL, as both the quality and quantity of the transferred cells have great influence on the outcome of TIL-based ACT (TIL-ACT). Considering the effects of cell reprogramming on senescence, we expected that the anti-tumor effect could be enhanced by TIL regeneration. To confirm this hypothesis, we established tumor-specific TIL-derived iPS cells (TIL-iPSC) with human colorectal cancer specimens. T cells differentiated from TIL-iPSC (TIL-iPS-T) retained not only intrinsic T cell functions and tumor specificity, but also exhibited improved proliferation capacity and additional killing activity. Moreover, less differentiated profiles and prolonged persistency were seen in TIL-iPS-T compared with primary cells. Our findings imply that iPSC technology has great potential for TIL-ACT.


Assuntos
Neoplasias Colorretais/terapia , Células-Tronco Pluripotentes Induzidas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias Colorretais/imunologia , Feminino , Humanos , Imunoterapia , Células-Tronco Pluripotentes Induzidas/citologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/citologia , Camundongos Endogâmicos NOD , Camundongos SCID , Linfócitos T/citologia , Linfócitos T/transplante
19.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070747

RESUMO

Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), ß1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-ß) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell-cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.


Assuntos
Neoplasias Colorretais/genética , Glicoesfingolipídeos/imunologia , Glicosiltransferases/genética , Mucinas/genética , Proteínas de Neoplasias/genética , Processamento de Proteína Pós-Traducional , Anexina A1/genética , Anexina A1/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Decorina/genética , Decorina/imunologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Regulação Neoplásica da Expressão Gênica , Glicoesfingolipídeos/metabolismo , Glicosilação , Glicosiltransferases/imunologia , Humanos , Imunoterapia Adotiva/métodos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia , Integrina beta1/genética , Integrina beta1/imunologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Mucinas/imunologia , Proteínas de Neoplasias/imunologia , Receptor fas/genética , Receptor fas/imunologia
20.
Biomed Pharmacother ; 140: 111752, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34044275

RESUMO

Inflammatory bowel disease (IBD) is characterized by intense immune dysregulation, gut microbiota imbalance, and intestinal epithelium destruction. Among the factors that contribute to the pathogenesis of IBD, lymphatics have received less attention, hence less studied, characterized, and explored. However, in recent years, the role of the lymphatic system in gastrointestinal pathophysiology continues to be highlighted. This paper examines the implications of lymphatic changes in IBD pathogenesis related to immune cells, gut microbiota, intestinal and mesenteric epithelial barrier integrity, and progression to colorectal cancer (CRC). Therapeutic targets of lymphatics in IBD studies are also presented. Available studies indicate that lymph nodes and other secondary lymphatic tissues, provide highly specialized microenvironments for mounting effective immune responses and that lymphatic integrity plays a significant role in small intestine homeostasis, where the lymphatic vasculature effectively controls tissue edema, leukocyte exit, bacterial antigen, and inflammatory chemokine clearance. In IBD, there are functional and morphological alterations in intestinal and mesenteric lymphatic vessels (more profoundly in Crohn's disease [CD] compared to ulcerative colitis [UC]), including lymphangiogenesis, lymphangiectasia, lymphadenopathy, and lymphatic vasculature blockade, affecting not only immunity but gut microbiota and epithelial barrier integrity. While increased lymphangiogenesis is primarily associated with a good prognosis of IBD, increased lymphangiectasia, lymphadenopathy, and lymphatic vessel occlusion correlate with poor prognosis. IBD therapies that target the lymphatic system seek to increase lymphangiogenesis via induction of lymphangiogenic factors and inhibition of its antagonists. The resultant increased lymphatic flow coupled with other anti-inflammatory activities restores gut homeostasis.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Vasos Linfáticos/imunologia , Animais , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/imunologia , Microbioma Gastrointestinal , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia
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