scholarly journals Inflammatory and regulatory T cells contribute to a unique immune microenvironment in tumor tissue of colorectal cancer patients

2012 ◽  
Vol 132 (8) ◽  
pp. 1842-1850 ◽  
Author(s):  
Adam Girardin ◽  
John McCall ◽  
Michael A. Black ◽  
Francesca Edwards ◽  
Vicky Phillips ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Tumor Tissue ◽  
Immune Microenvironment ◽  
Colorectal Cancer Patients

Novel CoupledCAR technology for treating colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2528-2528
Author(s):  
Lei Xiao ◽  
Song Li ◽  
Chengfei Pu ◽  
Zhiyuan Cao ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Complete Remission ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Lentiviral Vectors ◽  
Safety And Efficacy ◽  
Pet Ct ◽  
Colorectal Cancer Patients

2528 Background: Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited expansion in vivo. Methods: We designed a CAR lentivirus vector that consisted of a humanized CD19-specific single-chain variable fragment (scFv), a 4-1BB costimulatory domain, and a CD3ζ signaling domain.The lentivirus was produced by transfecting HEK-293T cells with CAR lentiviral vectors and viral packaging plasmids. Patient’s CD3 T cells was cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with CAR lentivirus at certain MOI 24h after stimulated by anti-CD3/CD28 magnetic beads. Transduction efficiency was evaluated at 7 to 9 days after CAR lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR,respectively. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results: We engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR-T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the metastatic colorectal cancer patients were infused with autologous anti-GCC CoupledCAR-T cells range from 4.9×105/kg to 2.9×106/kg. We observed that CoupledCAR-T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, and partial response.) was 57.1% (4/7), complete remission (CR) rate was 14.3% (1/7). Conclusions: In conclusion, the clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

scholarly journals Distribution of Regulatory T-Cells and Other Phenotypes of T-Cells in Tumors and Regional Lymph Nodes of Colorectal Cancer Patients

In Vivo ◽  
2020 ◽  
Vol 34 (2) ◽  
pp. 849-856
Author(s):  
KEISUKE KAZAMA ◽  
JUNYA OTAKE ◽  
TETSUTA SATOYOSHI ◽  
MANABU SHIOZAWA ◽  
NOBUHIRO SUGANO ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Cancer Patients ◽  
Regional Lymph Nodes ◽  
Colorectal Cancer Patients

CTLs/regulatory T-cells ratio as a prediction marker of chemotherapy in metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14684-e14684
Author(s):  
Teruo Sasatomi ◽  
Takafumi Oochi ◽  
Yutaka Ogata ◽  
Yoshito Akagi ◽  
Kazuo Shirouzu
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Metastatic Colorectal Cancer ◽  
Tumor Marker ◽  
Cancer Patients ◽  
Metastatic Lesion ◽  
The Other ◽  
Before And After ◽  
Colorectal Cancer Patients

e14684 Background: Many multiple anti cancer drugs regimens have been established for metastaticcolorectal cancer recently. We investigated cellular immunoreaction of these patients to their cancer. Methods: 32 metastatic colorectal cancer patients have been started chemotherapies. Their PBMCs were harvested and investigated their character by Fac scan with fluorescent labeled antibodies (CD3,CD8, CD4, CD25, Foxp3) at before and after chemotherapy. Results: After chemotherapy, both CTLs(CD3, CD8 positive) and regulatory T cells (CD4, CD25, Foxp3 positive) were decreased in number among all patients. On the other hand, CTL/T reg ratio were significantly increased among tumor marker decreased patients and significantly decreased among tumor marker increased or stable patients. CEA levels among 85.7% of increased CTL/T reg ratio patients became to decrease less thanhalf. CEA levels among 66.7% of decreased CTL/T reg ratio patients became to increase or to be stable, if their regimens have not been changed. The Reactive Rate of chemotherapy of CTL/T reg ratio increased patients was significantly higher than that of ratio decreased or stable patients. (P=0.021) The Disease Control Rate of chemotherapy of CTL/T reg ratio increased patients was higher than that of ratio decreased patients. Both resectability rate of liver metastatic lesion and early tumor shrinkage rate were higher at the CTL/T reg ratio increased patients group than at the other patients group. Conclusions: We found that the CTL/T reg ratios of PBMC in metastatic colorectal cancer patients were useful for prediction of the effect of chemotherapy.

Inclusion of BLIMP-1+ effector regulatory T cells improves the Immunoscore in a cohort of New Zealand colorectal cancer patients: a pilot study

2017 ◽  
Vol 66 (4) ◽  
pp. 515-522 ◽  
Author(s):  
Kirsten A. Ward-Hartstonge ◽  
John L. McCall ◽  
Timothy R. McCulloch ◽  
Ann-Kristin Kamps ◽  
Adam Girardin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
New Zealand ◽  
Pilot Study ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Colorectal Cancer Patients

Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner

2007 ◽  
Vol 57 (6) ◽  
pp. 813-821 ◽  
Author(s):  
Sheraz Yaqub ◽  
Karen Henjum ◽  
Milada Mahic ◽  
Frode L. Jahnsen ◽  
Einar M. Aandahl ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Dependent Manner ◽  
Immune Activity ◽  
Cox 2 ◽  
Colorectal Cancer Patients

Impact of antiangiogenic treatments on exhausted PD-1+ T lymphocytes in colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22121-e22121 ◽  
Author(s):  
Simon Pernot ◽  
Magali Terme ◽  
Elie Marcheteau ◽  
Thibault Voron ◽  
Orianne Colussi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Kinase Inhibitors ◽  
Anti Vegf ◽  
Colorectal Cancer Patients

e22121 Background: Tumors develop immunosuppressive mechanisms to escape the immune system. Among these mechanisms, T lymphocytes can express inhibitory molecules such as Program Death-1 (PD-1) protein which impair their activation and their effector functions. Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) that are routinely used as first- or second-line treatment of cancer patients, have been shown to modulate immunosuppressive mechanisms especially regulatory T cells. However, the role of specific VEGF/VEGFR blockade on PD-1 expression by T lymphocytes has not been studied. Methods: PD-1 expression on T lymphocytes has been analyzed by flow cytometry in a mouse model of colorectal cancer (CT26) treated by anti-angiogenic molecules targeting the VEGF-A/VEGFR axis and in the peripheral blood of metastatic colorectal cancer patients. Results: Sunitinib that directly targets VEGFR, PDGFR, c-kit, but also anti-VEGF-A antibody (the mouse orthologue of bevacizumab) decrease PD-1 expression on T lymphocytes infiltrating the tumors. Interestingly, anti-angiogenic treatments decrease the percentage of lymphocytes expressing not only PD-1 but also Tim-3 suggesting that the most exhausted T cells are targeted by anti-angiogenic treatments. Administration of masitinib, a TKI acting on KIT, PDGFR and FAK but not on the VEGF/VEGF-R pathway, was not able to modulate PD-1 expression on T cells. Finally, anti-VEGF-A treatment (bevacizumab) associated with chemotherapy decreases the proportion of PD-1+ CD4+T cells in the peripheral blood of metastatic colorectal cancer patients. Conclusions: These results show that anti-angiogenic treatments targeting VEGFA/VEGFR decrease PD-1-expressing T lymphocytes in colorectal cancer. These results suggest that VEGF-A could be involved in PD-1 expression and maybe in the induction of T lymphocyte exhaustion in colorectal cancer. We and others have shown that anti-angiogenic molecules could modulate other immunosuppressive populations such as regulatory T cells and myeloid suppressive cells, anti-angiogenic molecules might be efficiently associated with immunotherapeutic strategies in colorectal cancer.

scholarly journals Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2418
Author(s):  
Xuezhen Zeng ◽  
Simon E. Ward ◽  
Jingying Zhou ◽  
Alfred S. L. Cheng
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Cancer Patients ◽  
High Recurrence Rate ◽  
Immune Microenvironment ◽  
Liver Sinusoidal Endothelial Cells ◽  
Premetastatic Niche ◽  
Cancer Pathogenesis ◽  
Colorectal Cancer Patients ◽  
The Impact

A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention.

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