GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells<i>ex vivo</i>

Pedroza-González, Alexander; Zhou, Guoying; Singh, Simar Pal; Boor, Patrick P.C.; Pan, Qiuwei; Grünhagen, Dirk J.; Jonge, Jeroen de; Tran, T.; Verhoef, Cornelis; IJzermans, Jan N.M.; Janssen, Harry L.A.; Biermann, Katharina; Kwekkeboom, Jaap; Sprengers, Dave

doi:10.1080/2162402x.2015.1051297

Cited by 51 publications

(38 citation statements)

References 38 publications

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“…As a consequence, tumor-infiltrating Treg, 40 , 41 type 1 regulatory T cells 52 and probably other types of immune suppressor cells were also present in these assays. Therefore, the reported functional effects of checkpoint inhibitors on effector T cells in these assays may be partly indirect, mediated by effects of these antibodies on suppressor cells.…”

Section: Discussionmentioning

confidence: 90%

“…40 , 41 Myeloid dendritic cells (mDC) were isolated from patient autologous PBMC by depletion of CD19 + B cells followed by positive selection for BDCA-1 (BDCA-1 DC isolation kit, Miltenyi Biotec). mDC were cultured overnight with or without 20 µg/mL autologous tumor lysates or normal liver lysates, in the presence of 10 ng/mL granulocyte-macrophage colony-stimulating factor (Miltenyi Biotec) and 0.5 µg/mL polyinosinic: polycytidylic acid (InvivoGen, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…39 Previously we have observed that intra-tumoral CD8 + cytotoxic T cells (CTL) and CD4 + T helper cells (Th) are functionally compromised in LM-CRC, 40 and we also demonstrated that the suppression mediated by intra-tumoral regulatory T cells (Treg) in LM-CRC can be alleviated by blocking the inhibitory receptor CTLA4 and activating the stimulatory receptor GITR. 41 However, the expression and functional roles of inhibitory receptor-ligand pathways in regulating tumor-infiltrating effector T cell responses have not been studied yet in LM-CRC.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

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Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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“…We previously showed that engagement of GITR by GITRL reduced the suppression that HCC tumor‐derived Treg exert on blood‐derived CD4 + CD25 − T cells in ex vivo cultures . We now evaluated whether GITR ligation can enhance effector responses of HCC‐derived CD4 + and CD8 + TIL.…”

Section: Resultsmentioning

confidence: 99%

“…This is due to co‐inhibitory interactions, and to high numbers of conventional CD4 + FoxP3 + CD25 + regulatory T cells (Treg) and type 1 regulatory T cells present in liver tumors, which inhibit functions of effector T cells. We also demonstrated that agonistic targeting of GITR can alleviate the suppressive capacity of liver tumor‐derived CD4 + CD25 + Treg . However, the expression of GITR on cytotoxic CD8 + tumor‐infiltrating lymphocytes (TIL) and CD4 + FoxP3 − T helper cells (Th) in HCC patients is unknown.…”

Section: Introductionmentioning

confidence: 96%

GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

Beek

Zhou

Doukas

et al. 2019

Intl Journal of Cancer

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No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti‐PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co‐inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co‐stimulatory receptors might be able to stimulate anti‐tumor immunity in HCC is as yet unknown. We investigated whether agonistic targeting of the co‐stimulatory receptor GITR could reinvigorate ex vivo functional responses of tumor‐infiltrating lymphocytes (TIL) freshly isolated from resected tumors of HCC patients. In addition, we compared GITR expression between TIL and paired samples of leukocytes isolated from blood and tumor‐free liver tissues, and studied the effects of combined GITR and PD1 targeting on ex vivo TIL responses. In all three tissue compartments, CD4 + FoxP3 + regulatory T cells (Treg) showed higher GITR − expression than effector T‐cell subsets. The highest expression of GITR was found on CD4 + FoxP3 hi CD45RA − activated Treg in tumors. Recombinant GITR‐ligand as well as a humanized agonistic anti‐GITR antibody enhanced ex vivo proliferative responses of CD4 + and CD8 + TIL to tumor antigens presented by mRNA‐transfected autologous B‐cell blasts, and also reinforced proliferation, IFN‐γ secretion and granzyme B production in stimulations of TIL with CD3/CD28 antibodies. Combining GITR ligation with anti‐PD1 antibody nivolumab further enhanced tumor antigen‐specific responses of TIL in some, but not all, HCC patients, compared to either single treatment. In conclusion, agonistic targeting of GITR can enhance functionality of HCC TIL, and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC.

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Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

Hou,

Xu,

et al. 2023

BioFactors

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Immune checkpoints (ICPs) can promote tumor growth and prevent immunity‐induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD‐1) or cytotoxic T lymphocyte associated protein 4 (CTLA‐4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti‐PD‐1 and anti‐CTLA‐4 therapy. In particular, antigen presentation and interferon‐γ (IFN‐γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.

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GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

Cited by 51 publications

References 38 publications

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

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