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Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells [mCRC]

ABSTRACT: Colorectal tumors are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumor progression but are burdened by exhaustion mechanisms fueled by the tumor microenvironment, which must be counteracted to achieve control. Here, we deployed a multidimensional approach to unravel the T cell functional landscape in tumor and peritumoral tissues from primary colorectal cancers and liver metastases. We found that T-cells are mainly localized at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors and highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumors. By CRISPR/Cas9 genome editing tools, we simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting the HER-2 antigen, and disrupted CD39, thus generating triple-knockout engineered lymphocytes. We showed that the absence of CD39 confers HER2-specific T cells a functional advantage in eliminating HER2+ patient-derived organoids, starring the relevance of the CD39 axis for further exploitation in adoptive T-cell therapy strategies to treat primary and metastatic colorectal cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200129 | GEO | 2023/07/12

REPOSITORIES: GEO

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Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells [CRC]

Project description:Colorectal tumors are often densely infiltrated by immune cells that have a role in surveillance and modulation of tumor progression but are burdened by exhaustion mechanisms fueled by the tumor microenvironment, which must be counteracted to achieve control. Here, we deployed a multidimensional approach to unravel the T cell functional landscape in tumor and peritumoral tissues from primary colorectal cancers and liver metastases. We found that T-cells are mainly localized at the front edge and that tumor-infiltrating T cells co-express multiple inhibitory receptors and highlighted CD39 as the major driver of exhaustion in both primary and metastatic colorectal tumors. By CRISPR/Cas9 genome editing tools, we simultaneously redirected T-cell specificity employing a novel T-cell receptor targeting the HER-2 antigen, and disrupted CD39, thus generating triple-knockout engineered lymphocytes. We showed that the absence of CD39 confers HER2-specific T cells a functional advantage in eliminating HER2+ patient-derived organoids, starring the relevance of the CD39 axis for further exploitation in adoptive T-cell therapy strategies to treat primary and metastatic colorectal cancer.

2023-07-12 | GSE200130 | GEO

Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells [NanoString]

2023-07-12 | GSE200131 | GEO

CD39+ CD4+ conventional T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA4 blockade

Project description:CD4+ conventional T (Tconv) lymphocytes display an important role in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In mouse cancer models CD39+ Tconv cells accumulate with tumor growth but are absent in lymphoid organs. Compared to tumor CD39- Tconv cells, CD39+ cells exhibit a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of co-inhibitory receptors and transcription factors related to exhaustion. Additionally, CD39+ Tconv cells show an increased production of INFg, Granzyme B, Perforin and CD107a, but a reduced production of TNF upon in vitro stimulation. In vivo, CTLA-4 blockage induces the expansion of CD39+ Tconv cells in the tumor, while maintaining their features of cytotoxicity and exhaustion. In breast cancer patients, CD39+ Tconv cells are found in tumors, and at lower frequency in the adjacent non-tumoral mammary tissue. CD39+ Tconv cells are also present in metastatic but not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constitute a heterogeneous cell population with features of exhaustion, impaired TNF production, and high expression of co-inhibitory receptors and CD107a. High gene expression of CD4 and ENTPD1 (CD39) in human tumor tissues correlates with higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of CD4+ T cells with characteristics of both exhaustion and cytotoxic potential and put forward CD39+ Tconv cells as pivotal players of the immune response against tumors.

2024-01-01 | GSE221881 | GEO

Gene signature predictive of response to chemotherapy in mCRC [array]

2013-12-01 | E-GEOD-52735 | biostudies-arrayexpress

CD39 expression identifies terminally exhausted CD8+ T cells

Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).

2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress

Gene signature predictive of response to chemotherapy in mCRC [RT-PCR]

Project description:The objective is to generate a robust and validated predictor profile for chemotherapy response in patients with mCRC using microarray gene expression profiles of primary colorectal cancer tissue. To define a gene signature of response to chemotherapy in metastatic colorectal cancer, samples were obtained from 40 patients from Marques de Valdecilla Hospital who underwent primary surgery. Gene expression was detected and quantified using the Human Whole Genome U133 Plus 2.0 array (Affymetrix), containing 54675 human gene probes. The validation set consisted of 119 samples from Hospital Virgen del Rocio, Seville, Spain; Hospital Virgen de la Victoria, Malaga, Spain; Hospital de la Merced, Osuna, Spain and Hospital MarquM-CM-)s de Valdecilla, Santander, Spain, and included 86 tumor samples (40 coming from the training set and 46 from newly treated CRC patients) and 33 normal tissue samples of CRC patients used as controls. Custom-designed TaqManM-BM-. Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards including the 161 genes selected for validation were run and analyzed by the ABI PRISMM-BM-. 7900HT Sequence Detection System (SDS 2.2, Applied Biosystems) according to manufacturer's protocol (Applied Biosystems). Expression of target miRNAs was normalized in relation to the expression of GAPDH. Cycle threshold (Ct) values were calculated using the SDS software v.4.2 using automatic baseline settings and a threshold of 0.2. Relative quantification of gene expression was calculated by the 2M-bM-^HM-^RM-NM-^TCt method (Applied Biosystems user bulletin no. 2 (P/N 4303859)). This submission represents the RT-PCR component of the study only

2013-11-20 | E-GEOD-52513 | biostudies-arrayexpress

CD39 Identifies Tumor-Reactive CD8 T cells in Patients With Lung Cancer [VDJ]

Project description:We utilized cell surface expression of CD39 to demonstrate that this marker enriches for CD8+ T cells with features of exhaustion, proliferation and tumor reaxtivity.

2022-11-17 | GSE218261 | GEO

CD39 Identifies Tumor-Reactive CD8 T cells in Patients With Lung Cancer [FB]

Project description:We utilized cell surface expression of CD39 to demonstrate that this marker enriches for CD8+ T cells with features of exhaustion, proliferation and tumor reaxtivity.

2022-11-17 | GSE218259 | GEO

CD39 Identifies Tumor-Reactive CD8 T cells in Patients With Lung Cancer [scRNA]

Project description:We utilized cell surface expression of CD39 to demonstrate that this marker enriches for CD8+ T cells with features of exhaustion, proliferation and tumor reaxtivity.

2022-11-17 | GSE218258 | GEO

A Population of Tumor-Infiltrating CD4+ T-cells Co-expressing CD38 and CD39 is Associated with Checkpoint Inhibitor Resistance

Project description:We previously showed that elevated peripheral blood frequencies of a population of T-cells defined by the marker set CD3+CD4+CD127-GARP-CD38+CD39+ were associated with checkpoint immunotherapy resistance in metastatic melanoma patients. In this study we sought to further understand the role(s) of this population of ectoenzyme expressing T-cells (Teee). Using RNA-sequencing and flow cytometry to evaluate Teee from the peripheral blood of metastatic melanoma patients, we found that Teee were proliferative, apoptotic, had exhaustion associated phenotypes, and had high expression of inhibitory molecules. Co-culture of patient Teee with autologous T-cells in vitro resulted in suppression of proliferation of the target T-cells. Using single-cell RNA-sequencing datasets, we identified distinct clusters of cells with a Teee gene signature present in melanoma, non-small cell lung cancer and bladder cancer patients’ tumors. Teee were not present in healthy bladder tissue. Using multispectral immunofluorescence of melanoma patient FFPE tumor samples, we were able to identify CD4+ T-cells co-expressing CD38 and CD39 in the tumor microenvironment, which preferentially associated with Ki67- CD8+ T-cells. Finally, we found that high baseline intra-tumor frequencies of cells with a Teee gene signature were associated with checkpoint immunotherapy resistance and poor overall survival in metastatic melanoma patients. These results build upon our previous findings, demonstrating that a novel population of CD4+ T-cells co-expressing CD38 and CD39 are found in the periphery and tumor of patients and are associated with checkpoint immunotherapy resistance.

2023-07-17 | GSE224099 | GEO

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