apyrase and Colorectal-Neoplasms

CD39 (nucleoside triphosphate diphosphohydrolase) and Ecto-5-nucleotidase (CD73) have been recognized as important factors mediating various pathological and physiological responses in the tumor microenvironment. Elevated expression of CD73 and CD39 is correlated with the over-production of adenosine in the tumor region. This increase is associated with an immunosuppressive state in the tumor site that enhances various tumor hallmarks such as metastasis, angiogenesis, and cell proliferation. Adenosine promotes these behaviors through interaction with four adenosine receptors, including A3R, A2BR, A2AR, and A1R. Signaling of these receptors reduces the function of immune effector cells and enhances the expansion and function of tumor-associated immune cells. Several studies have been shown the important role of adenosine/CD73/CD39/ARs axis in the immunopathogenesis of colorectal cancer. These findings imply that components of this axis can be considered as a worthy target for colorectal cancer immunotherapy. In this review, we summarized the role of CD73/CD39/adenosine/ARs in the immunopathogenesis of colorectal cancer.

Topics: 5'-Nucleotidase; Adenosine; Animals; Antigens, CD; Apyrase; Colorectal Neoplasms; Humans; Receptors, Purinergic P1

Colorectal tumours are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumour progression but are burdened by immunosuppressive signals, which might vary from primary to metastatic stages. Here, we deployed a multidimensional approach to unravel the T-cell functional landscape in primary colorectal cancers (CRC) and liver metastases, and genome editing tools to develop CRC-specific engineered T cells.. We paired high-dimensional flow cytometry, RNA sequencing and immunohistochemistry to describe the functional phenotype of T cells from healthy and neoplastic tissue of patients with primary and metastatic CRC and we applied lentiviral vectors (LV) and CRISPR/Cas9 genome editing technologies to develop CRC-specific cellular products.. We found that T cells are mainly localised at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors, which largely differ from primary to metastatic sites. Our data highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumours. We thus simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting HER-2 and disrupted the endogenous TCR genes (TCR editing (TCR. HER-2-specific CD39 disrupted engineered T cells are promising advanced medicinal products for primary and metastatic CRC.

Topics: Antigens, CD; Apyrase; Cell Engineering; Colorectal Neoplasms; Humans; Liver Neoplasms; Receptors, Antigen, T-Cell; T-Lymphocytes

Angiogenesis pathway genes show substantial genetic variability causing inter-individual differences in responses to anti-angiogenic drugs. We examined 20 single nucleotide polymorphisms (SNPs) in 13 of these genes to predict tumour response and clinical outcome measured as progression free survival (PFS) and overall survival (OS) in 57 patients with metastatic colorectal cancer (mCRC) given bevacizumab plus chemotherapy. SNPs were detected (iPLEX® Assay) in genomic DNA extracted from formalin-fixed paraffin-embedded tumour specimens. The variant allele

Topics: Adult; Aged; Aged, 80 and over; Angiopoietin-1; Antineoplastic Combined Chemotherapy Protocols; Apyrase; Bevacizumab; Biomarkers, Tumor; Biopsy; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fibroblast Growth Factor 2; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Neovascularization, Pathologic; Polymorphism, Single Nucleotide; Progression-Free Survival; Retrospective Studies

Microsatellite-stable (MSS) colorectal cancers are characterized by low mutation burden and limited immune-cell infiltration and thereby respond poorly to immunotherapy. Here, we report a case of metastatic MSS colorectal cancer with a robust anticancer immune response. The primary tumor was resected in 2012, and the patient received several cycles of chemotherapy until 2017. In 2018, the patient underwent a left hepatectomy to remove a new metastasis. Analysis of the metastatic tumor revealed a strong CD8

Topics: Antigens, CD; Antineoplastic Agents; Apyrase; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Hepatectomy; Humans; Integrin alpha Chains; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged

The γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarize to CD39+γδ Tregs upon colorectal cancer (CRC) induction, and the underlying mechanism remains unclear. Here, we show that the frequency of CD39+γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided CRC (RSCRC) than in the left-sided CRC (LSCRC). Interestingly, CD39+γδ Tregs from RSCRC showed stronger immunosuppressive phenotype and function than LSCRC. Furthermore, the quantitative mass spectrometry data show that CD39+γδ Treg polarization was related to the abnormal activation of the Phospholipase a2-IVa/Arachidonic acid (PLA2G4A/AA) metabolic pathway in RSCRC. Using an in vitro coculture system and an orthotopic murine model of CRC, we show that the overexpression of Pla2g4a in CT26 cells induced CD39+γδ Tregs, inhibiting the antitumor immune response. Finally, we found that the overall survival of the PLA2G4Ahi group was significantly shortened compared with PLA2G4Alo RSCRC, while the survival of LSCRC showed the opposite. Collectively, RSCRC with abnormal PLA2G4A expression educates γδ T cells into CD39+γδ Tregs to promote tumor progression and metastasis. Our work highlights the interaction between cancer cells and immune cells by distinguishing the primary tumor site and deepens the understanding of the tumor microenvironment and immunosuppression.

Topics: Aged; Animals; Apyrase; Coculture Techniques; Colorectal Neoplasms; Datasets as Topic; Disease Models, Animal; Disease Progression; Female; Group IV Phospholipases A2; Humans; Intestinal Mucosa; Intraepithelial Lymphocytes; Kaplan-Meier Estimate; Lymphocyte Activation; Male; Mice; Middle Aged; Primary Cell Culture; Tumor Cells, Cultured; Tumor Microenvironment

Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show

Topics: Antigens, Bacterial; Antigens, CD; Apyrase; CD4 Antigens; Cell Line, Tumor; Colorectal Neoplasms; Forkhead Transcription Factors; Gastrointestinal Microbiome; Humans; Lymphocyte Activation; Mucosal-Associated Invariant T Cells; Receptors, Antigen, T-Cell

Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.. We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.. In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.. Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

Topics: 5'-Nucleotidase; Adenosine; Antineoplastic Combined Chemotherapy Protocols; Apyrase; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cetuximab; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; GPI-Linked Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Receptors, Purinergic P1; Survival Rate

Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types

Topics: Antigens, Neoplasm; Antigens, Viral; Apyrase; Bystander Effect; CD8-Positive T-Lymphocytes; Cell Separation; Colorectal Neoplasms; ErbB Receptors; Humans; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Phenotype

Expression of the ENTPD5/mt-PCPH onco-protein and overexpression of the normal ENTPD5/PCPH protein contribute to the malignant transformation of diverse mammalian cell types, and PCPH is mutated and/or deregulated in various human tumor types. Expression of PCPH or mt-PCPH caused similar phenotypes, yet the effects promoted by mt-PCPH expression were consistently and substantially greater. ATP depletion and increased stress‑resistance are phenotypes commonly associated with PCPH and mt-PCPH expression. It was suggested that the intrinsic nucleoside triphosphate diphosphohydrolase (NTPDase) activity of PCPH and mt-PCPH may be responsible for these phenotypes, but direct supporting evidence remains to be established. Results from experiments designed to test such hypothesis demonstrate that, as expected, mt-PCPH expression in human colorectal carcinoma (CRC) cells decreased their ATP levels and conferred resistance to oxaliplatin, a colorectal cancer-relevant chemotherapeutic agent. Using a combination of site-directed mutagenesis, immunoprecipitation methods, in vitro enzyme activity assays and in situ enzyme activity determinations in live cells, this report also demonstrates that the mt-PCPH oncoprotein lacks detectable NTPDase activity, indicating that direct ATP cleavage by mt-PCPH did not cause the ATP depletion observed in mt-PCPH-expressing CRC cells. These results strongly suggest that the mt-PCPH oncoprotein may regulate the cellular energy levels and subsequent chemoresistance by an NTPDase-independent mechanism. Understanding possible alternative mechanisms will be essential to devise strategies for the successful treatment of predictably therapeutically resistant tumors expressing either increased PCPH levels or, particularly, the mt-PCPH oncoprotein.

Topics: Adenosine Triphosphate; Animals; Antigens, CD; Apyrase; Carcinogenesis; Catalysis; Cell Line, Tumor; Colorectal Neoplasms; Humans; Mutagenesis, Site-Directed; Oncogene Proteins; Pyrophosphatases