Cytotoxic chemotherapy reduces T�cell trafficking to the spleen by downregulating the expression of C‑C motif chemokine ligand 21 and C‑C motif chemokine ligand 19

Liu, Lina; Zhao, Li; Yang, Yang; Gao, Jianbao; Hu, Chunyan; Guo, Bo; Zhu, Bo

doi:10.3892/ol.2018.9287

Cited by 3 publications

(4 citation statements)

References 32 publications

(52 reference statements)

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“…CXCR7/C-X-C motif chemokine receptor 4 heterodimer-induced histone demethylation promotes colorectal tumorigenesis (43). In addition, CCL21 is involved in T-cell migration and trafficking to secondary lymphoid organs (44). The present study revealed that CDK9 expression was positively correlated with CXCL12, ACKR3 (also referred to as CXCR7 ) and CCL21 expression, suggesting that CDK9 may inhibit CD8 + T cell infiltration via the CXCL12/CXCR7 axis.…”

Section: Discussionmentioning

confidence: 99%

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

et al. 2019

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Programmed death 1 (PD-1)-targeted therapy has benefited patients with microsatellite instability-high metastatic colorectal cancer (mCRC). However, the efficacy of PD-1-targeted therapy is poor in patients with microsatellite-stable (MSS) mCRC. Therefore, it is imperative to explore additional co-inhibitory molecular signalling pathways to improve the efficacy of immunotherapy in MSS mCRC treatment. In the present study, the association between cyclin-dependent kinase 9 (CDK9) expression and the survival of patients with CRC was analysed using RNA sequencing data from 605 patients, including 121 cases of mortality, from human cancer datasets. Furthermore, 35 clinical MSS stage III–IV CRC specimens were collected to assess CDK9 protein expression by immunohistochemistry, and the frequency of tumor-infiltrating CD8+ T cells was assessed by flow cytometry. The human cancer datasets demonstrated that upregulation CDK9 significantly shortened the survival of patients with stage II–IV colon cancer. Additionally, CDK9 mRNA expression was positively correlated with the expression levels of genes associated with immune evasion in the tumor. Notably, CDK9 was expression was upregulated in stage IV CRC compared with para-cancerous tissues and early-stage tumors. Interestingly, CDK9 expression was negatively associated with the infiltration of CD8+ T cells at the tumor site. In addition, the expression levels of T-cell immunoglobulin mucin family member 3 and CD39, proteins associated with exhaustion, on tumor-infiltrating CD8+ T cells were significantly elevated in patients with abnormal CDK9 expression levels. The present study demonstrated that CDK9 expression was negatively associated with CD8+ T cell infiltration and positively associated with CD8+ T cell exhaustion in MSS mCRC. In conclusion, CDK9 may be utilized to evaluate the prognosis and the immune-type of the tumor microenvironment in patients with MSS mCRC.

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Section: Discussionmentioning

confidence: 99%

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

et al. 2019

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“…Conversely, the degree of TIL infiltration of colorectal cancer liver metastases was not associated with the prognosis in patients with a long-term preoperative chemotherapy. According to previous studies, long-term chemotherapy may change the local immunity in liver metastases and reduce the prognostic value of the density of TILs (20,(32)(33)(34)(35)(36)(37)(38). There may be some possible causes to this observation.…”

Section: Discussionmentioning

confidence: 97%

“…Firstly, the dysfunction of lymphocytes may be involved. Long-term chemotherapy induces a reduction in the absolute number of lymphocytes and prevents the induction of lymphocytes to secondary lymphoid organs, resulting in decreased lymphocyte activation and thereby weakening the T cell immune response (32). A study by Wu et al (20) using an experimental mouse model demonstrated that the short-term administration of fluorouracil can increase the proliferation and cytotoxicity of CD8 + T cells, while repeated administration causes a decrease in the proliferation and cytotoxicity of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of the density of tumor‑infiltrating lymphocytes in colorectal cancer liver metastases

et al. 2021

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Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the anti-tumor immune status of patients and to be correlated with their prognosis and therapeutic outcomes. However, the characteristics of the local immune status in metastatic tumors is poorly understood, as primary tumors have been the focus in most previous studies. In addition, the local immune status may be influenced by preoperative chemotherapy. The present study aimed therefore to investigate the relationship between the degree of TIL infiltration and the prognosis in patients with curative resection of colorectal cancer liver metastases and to examine the effects of preoperative chemotherapy on the function of immune cells. A total of 108 patients who underwent curative resection of colorectal cancer liver metastases in our department between May 1996 and January 2017 were enrolled in the present study. Peripheral blood samples were obtained within two weeks before surgery. TIL infiltration was evaluated by immunohistochemical staining of surgically resected specimens of liver metastases using anti-CD8/CD3 antibodies. The mean number of TILs in five different fields was calculated, and patients were classified into a high-TIL group and a low-TIL group. Furthermore, patients were divided into three groups as follows: i) A group of patients who did not receive preoperative chemotherapy; ii) a group of patients who received short-term preoperative chemotherapy for <6 months; and iii) a group of patients who received long-term preoperative chemotherapy for ≥6 months. The results demonstrated that the density of TILs in colorectal liver metastases was not correlated with the absolute peripheral lymphocyte count in all patients. Furthermore, the degree of CD8 + TIL infiltration in liver metastases was significantly lower in the recurrence group compared with the recurrence-free group following hepatectomy. In all patients with colorectal liver metastases, the degree of CD8 + TIL infiltration was significantly associated with the relapse-free and overall survival. In patients without preoperative chemotherapy, the degree of CD8 + TIL infiltration was significantly associated with the relapse-free survival, and a high CD8 + TIL presence tended to have a better effect on the overall survival than a low CD8 + TIL presence. In the short-term chemotherapy group, the degree of CD8 + TIL infiltration was significantly associated with the relapse-free and overall survival. In the long-term chemotherapy group, there were no significant differences between the high-and low-CD8 + TIL groups in the relapse-free and overall survival. In contrast to CD8 + TILs, CD3 + TILs showed a poor prognostic ability. In summary, the degree of CD8 + TIL infiltration in colorectal cancer liver metastases may be correlated with patient prognosis. However, in patients who received long-term chemotherapy before surgery, the degree of TIL infiltration was not necessarily associated with prognosis as the anti-tumor effects of TILs may decrease. The degree of CD8 + TIL infilt...

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“…As these anticancer drugs have toxic adverse effects on normal cells and cause immunosuppression, considerable caution is needed prior to their use. In particular, repeated cycles of chemotherapy affect the function of lymphocytes and decrease T cell-mediated immune responses [8,9]. Therefore, before repurposing FBZ as an anticancer drug, it is important to evaluate its cytotoxic effects on cancer cells…”

Section: Introductionmentioning

confidence: 99%

Differential cytotoxic effects of fenbendazole on mouse lymphoma EL-4 cells and spleen cells

2023

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Fenbendazole (FBZ) is a benzimidazole anthelmintic widely used to treat parasitic infections. The anticancer effect of FBZ has been recently highlighted leading to its consideration as a potential anticancer agent. Although previous studies have demonstrated the effect of FBZ on cancer cells, there is a paucity of studies on the effect of FBZ on lymphoma cells and normal immune cells. Herein, we investigated the effects of FBZ on a mouse lymphoma cell line, EL-4 cells, and spleen cells, using vincristine as a positive control. The cellular metabolic activity of EL-4 cells was decreased by FBZ, but that of the spleen cells was not decreased. Moreover, FBZ reduced the mitochondrial membrane potential and induced reactive oxygen species production in EL-4 cells, but not in spleen cells. FBZ induced G2/M phase arrest and increased the sub G0/G1 phase ratio, indicating apoptosis. Furthermore, compared to the control cells, the reactivity of spleen cells pretreated with FBZ to lipopolysaccharide was maintained. In summary, FBZ is cytotoxic to EL-4 cells, but not to spleen cells. This study provides experimental evidence that FBZ exerts an anticancer effect, and less cytotoxic effects and functional damage to normal spleen cells.

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Cytotoxic chemotherapy reduces T�cell trafficking to the spleen by downregulating the expression of C‑C motif chemokine ligand 21 and C‑C motif chemokine ligand 19

Cited by 3 publications

References 32 publications

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

Prognostic value of the density of tumor‑infiltrating lymphocytes in colorectal cancer liver metastases

Differential cytotoxic effects of fenbendazole on mouse lymphoma EL-4 cells and spleen cells

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