Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy

Dama, Paola; Tang, Marshall; Fulton, Noreen; Kline, Justin; Liu, Hongtao

doi:10.1186/s40425-019-0611-3

Cited by 63 publications

(54 citation statements)

References 27 publications

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“…Many factors including immunosuppressive cells, cytokines and chemokines contribute to drug resistance in the tumor microenvironment [6, 7]. Higher infiltration of regulatory T cells (Tregs) could be significantly correlated with resistance to antiangiogenic therapy in metastatic renal cell carcinoma [8].…”

Section: Introductionmentioning

confidence: 99%

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Wang¹,

Yang²,

Yu³

et al. 2019

j. immunotherapy cancer

138

116

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Background Colorectal cancer (CRC) is one of the most common forms of cancer worldwide. The tumor microenvironment plays a key role in promoting the occurrence of chemoresistance in solid cancers. Effective targets to overcome resistance are necessary to improve the survival and prognosis of CRC patients. This study aimed to evaluate the molecular mechanisms of the tumor microenvironment that might be involved in chemoresistance in patients with CRC. Methods We evaluated the effects of CCL20 on chemoresistance of CRC by recruitment of regulatory T cells (Tregs) in vitro and in vivo. Results We found that the level of CCL20 derived from tumor cells was significantly higher in Folfox-resistant patients than in Folfox-sensitive patients. The high level of CCL20 was closely associated with chemoresistance and poor survival in CRC patients. Among the drugs in Folfox chemotherapy, we confirmed that 5-FU increased the expression of CCL20 in CRC. Moreover, CCL20 derived from 5-FU-resistant CRC cells promoted recruitment of Tregs. Tregs further enhanced the chemoresistance of CRC cells to 5-FU. FOXO1/CEBPB/NF-κB signaling was activated in CRC cells after 5-FU treatment and was required for CCL20 upregulation mediated by 5-FU. Furthermore, CCL20 blockade suppressed tumor progression and restored 5-FU sensitivity in CRC. Lastly, the expression of these signaling molecules mediating chemoresistance was closely correlated with poor survival of CRC patients. Conclusions CRC cell-secreted CCL20 can recruit Tregs to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling, indicating that the FOXO1/CEBPB/NF-κB/CCL20 axis might provide a promising target for CRC treatment. Electronic supplementary material The online version of this article (10.1186/s40425-019-0701-2) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Wang¹,

Yang²,

Yu³

et al. 2019

j. immunotherapy cancer

138

116

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“…Another “non-classical” LSC biomarker is T-cell immunoglobulin and mucin 3 (TIM-3), that is highly expressed on LSCs but not expressed on healthy HSCs ( 498 ). It is correlated to a poor prognosis ( 420 ) and treatment failure ( 423 ). Stem cell properties of TIM-3 + cells were confirmed by engraftment in a xenograft mouse model ( 421 ).…”

Section: Cscs and Their Origin At Tumor Initiationmentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

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“…Several studies reported increased levels of PD-1 as well as multiple co-expressing inhibitor receptors (IRs) on CD8 + T cells of AML patients at diagnosis [18,19]. Longitudinal observation of changes in the IRs expression pattern indicate that PD-1 and Tim3, together with several other coinhibitory receptors, are increased in bone marrow CD8 + T cells in non-responders and reduced in responders post chemotherapy [2,36]. Our analysis of TCRβ sequences showed that TCRβ clonotypes in CD8 + PD-1 + populations were more oligoclonal than those in CD8 + PD-1 − T populations.…”

Section: Discussionmentioning

confidence: 99%

Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

Feng

Fang

Kuang

et al. 2020

Preprint

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Background: CD8+ T cells are crucial adaptive immune effectors and express receptors (T cell receptors, TCRs) that specifically recognize and eradicate tumor cells. The diversity of the TCR repertoire is generated by specialized genetic diversification mechanisms, leading to an extremely variable TCR repertoire capable of recognizing a wide range of antigens. However, the variations in CD8+ TCR diversity and their clinical implications in AML patients remain unknown.Methods: CD8+ T cells in 10 healthy donors and 31 AML patients at diagnosis and after chemotherapy were enriched using the Dynabeads CD8 Positive Isolation Kit. Flow cytometry were used for PD-1 expression level analysis of CD8+ T cells and CD8+PD-1+ and CD8+PD-1- T cell sorting. TCRβ deep sequencing was performed to analysis the CD8+ T cells clonal expansion and TCR repertoire diversity.Results: Diminished TCR repertoire diversity and expansional T cell clones were noted in the bone marrow of AML patients. In relapsed patients, T cells were found to be more clonally expanded post chemotherapy when compared to new diagnosis. Moreover, more significantly expanded TCRβ clonotypes were noted in CD8+ PD-1+ T cells than in CD8+ PD-1- T cells regardless of the time point of examination. Conclusions: Our systematic T-cell repertoire analysis may help better characterize CD8+ T cells pre- and post-chemotherapy in AML, which may provide insights into therapeutic strategies in hematological malignancies.

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Gal9/Tim-3 expression level is higher in AML patients who fail chemotherapy

Cited by 63 publications

References 27 publications

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Clonal Expansion of Bone Marrow CD8+ T Cells in Acute Myeloid Leukemia Patients at New Diagnosis and Post Chemotherapy

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