CD4+CD25+CD127low Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Sharma, Shreya; Khosla, Ritu; David, Paul; Rastogi, Archana; Vyas, Ashish Kumar; Singh, Dileep; Bhardwaj, Ankit; Sahney, Amrish; Maiwall, Rakhi; Sarin, Shiv Kumar; Trehanpati, Nirupma

doi:10.3389/fimmu.2015.00049

Cited by 35 publications

(35 citation statements)

References 29 publications

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“…Tregs inhibit anti-tumor immunity of CD8 + T cells [ 6 – 9 ]. To test whether AR mediated activation of Tregs is involved in regulating anti-tumor immunity, CD8 + T cells and Tregs were isolated from the Hepa1–6 xenografts and pooled.…”

Section: Resultsmentioning

confidence: 99%

“…A subpopulation of CD4 + T cells that express CD25 and the master transcriptional factor Foxp3, termed regulatory T cells (Tregs), play a crucial role in promoting tumor growth and progress by inhibiting anti-tumor CD8 + T cells [ 3 – 5 ]. Although previous observations have demonstrated the function of Tregs in inhibiting anti-tumor CD8 + T cells in HCC [ 6 – 9 ], the underlying cellular and molecular mechanisms concerning the activation of Tregs still remain largely unknown. Most of the previous studies focused on either how Tregs suppress tumor-associated antigen (TAA) specific effector T cell function, or how Tregs regulate tumor-associated inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells

et al. 2015

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CD8+ T cell-mediated immune response plays an important role in inhibiting progression of hepatocellular carcinoma (HCC). For strategic immunotherapy, it is critical to understand why some of the tumor cells escape from this immune attack. In this study, we investigated how HCC cells alter endogenous anti-tumor immunity and their related signaling pathways. We found that HCC cells, both in vitro and in vivo, substantially secret and express amphiregulin (AR). AR in turn activates immunosuppressive function of intratumoral CD4+Foxp3+ regulatory T cells (Tregs), a major inhibitor of CD8+ T cells. Using either lentiviral siRNA, or AR neutralizing antibody, we blocked the expression and function of AR to test the specificity of AR mediated activation of Tregs, Biochemical and cell biology studies were followed and confirmed that blocking of AR inhibited Tregs activation. In addition, we found that AR can trigger the activation of rapamycin complex 1(mTORC1) signaling in Tregs. The mTORC1 inhibitor rapamycin treatment led to compromise Treg function and resulted in enhancing anti-tumor function of CD8+ T cells. Blocking AR/EGFR signaling in Tregs with Gefitinib also enhanced anti-tumor immunity and decreased tumor size in a mouse xenograft tumor model. Taken together, our study suggested a novel mechanism of functional interaction between HCC and Tregs for regulating anti-tumor function of CD8+ T cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells

et al. 2015

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“…It seems that Tregs have differential influence at different stages of CRC development. Excessive activation of Tregs also contributes to persistent HBV infection and progression of HCC [9] and HBV + HCC patients have Tregs with greater suppressive potential than non-HBV + HCC patients [10]. Negative role of Tregs through dampening favorable CD8 + T cell responses to tumor associated antigens has been reported in breast cancer patients and patients with low CD8 + T cells/Tregs ratio had a better survival benefit [11].…”

Section: Immunosuppression By Tregsmentioning

confidence: 99%

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

Kalathil

Thanavala

2016

Cancer Immunol Immunother

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A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism which prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert to cause the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune based therapeutic interventions of cancer. Multi-pronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8+ T cells and increase the number of IFN-γ producing CD4+ T cells.

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“…Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and is one of the deadliest cancers in Asia (1–3). Current curative approaches for liver cancer mainly involve partial liver resection, liver transplantation, chemotherapy, and transarterial chemoembolization (4, 5).…”

Section: Introductionmentioning

confidence: 99%

Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma

Jiang

Chen³

et al. 2017

Front. Immunol.

159

128

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BackgroundThe lack of a general clinic-relevant model for human cancer is a major impediment to the acceleration of novel therapeutic approaches for clinical use. We propose to establish and characterize primary human hepatocellular carcinoma (HCC) xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR) T cells and accelerate the clinical translation of CAR T cells used in HCC.MethodsPrimary HCCs were used to establish the xenografts. The morphology, immunological markers, and gene expression characteristics of xenografts were detected and compared to those of the corresponding primary tumors. CAR T cells were adoptively transplanted into patient-derived xenograft (PDX) models of HCC. The cytotoxicity of CAR T cells in vivo was evaluated.ResultsPDX1, PDX2, and PDX3 were established using primary tumors from three individual HCC patients. All three PDXs maintained original tumor characteristics in their morphology, immunological markers, and gene expression. Tumors in PDX1 grew relatively slower than that in PDX2 and PDX3. Glypican 3 (GPC3)-CAR T cells efficiently suppressed tumor growth in PDX3 and impressively eradicated tumor cells from PDX1 and PDX2, in which GPC3 proteins were highly expressed.ConclusionGPC3-CAR T cells were capable of effectively eliminating tumors in PDX model of HCC. Therefore, GPC3-CAR T cell therapy is a promising candidate for HCC treatment.

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CD4+CD25+CD127low Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma

Cited by 35 publications

References 29 publications

Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells

Amphiregulin activates regulatory T lymphocytes and suppresses CD8+ T cell-mediated anti-tumor response in hepatocellular carcinoma cells

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma

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