TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Ge, Zhouhong; Zhou, Guoying; Carrascosa, Lucia Campos; Gausvik, Erik; Boor, Patrick P.C.; Noordam, Lisanne; Doukas, Michael; Polak, Wojciech; Terkivatan, Türkan; Pan, Qiuwei; Takkenberg, R. Bart; Verheij, Joanne; Erdmann, Joris I.; IJzermans, Jan N.M.; Kraan, Jaco; Kwekkeboom, Jaap; Sprengers, Dave

doi:10.1016/j.jcmgh.2021.03.003

Cited by 59 publications

(57 citation statements)

References 50 publications

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“…Knockdown of TIGIT was able to restore in vitro IFN-g and TNF-a production by circulating CD8 + T cells from AML patients (62). Nevertheless, single TIGIT blockade achieved no or moderate anti-tumor efficacy in experimental tumor models (37,52,58,64) and in enhancing in vitro functionality of human tumor-infiltrating CD8 + T cells (31). However, since CD155-TIGIT interaction contributes to cancer resistance to PD-1 blockade (35,36), inhibition of TIGIT may be a promising strategy to increase the efficacy of PD-1 blockade therapy, especially to combat PD-1 inhibitor resistant tumors (37).…”

Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

“…CD155 is expressed on monocytes, dendritic cells (DCs), fibroblasts and endothelial cells, both in healthy tissues and in tumors. Additionally, CD155 is over-expressed on cancer cells in human malignancies including colon cancer (26), lung adenocarcinoma (27), melanoma (28), pancreatic cancer (29), glioblastoma (30) and hepatocellular carcinoma (31). Apart from its normal function in establishing cell-cell adhesion (32,33), it also functions as the receptor of polio virus (34).…”

Section: Tigit Structure Expression and Ligandsmentioning

confidence: 99%

“…TIGIT is expressed on human tumor-infiltrating CD8 + T cells, NK cells, Th and Treg cells in melanoma (54,55), NSCLC (56,57), colon cancer (52), HCC (31,58), gastric cancer (59), glioblastoma (60) and hematological malignancies (42,61,62). Increased numbers of intra-tumoral TIGIT + CD4 + and CD8 + T cells are associated with inferior patient outcomes and poor survival in follicular lymphoma patients (61).…”

Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

“…TIGIT is coordinately expressed with PD-1 on human and murine CD8 + TILs (52,54,58,65,66), whereas CD226 expression is negatively associated with PD-1 expression on CD8 + TILs (31,54). In mouse tumors, TIGIT marks a dysfunctional subset of CD8 + TILs that co-expresses high levels of PD-1 and TIM3 (66,67).…”

Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

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TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

et al. 2021

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T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance. While single TIGIT blockade has limited anti-tumor efficacy, pre-clinical studies indicate that co-blockade of TIGIT and PD-1/PD-L1 pathway leads to tumor rejection, notably even in anti-PD-1 resistant tumor models. Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. In this review, we summarize the current knowledge and identify the gaps in our current understanding of TIGIT’s roles in cancer immunity, and provide, based on these insights, recommendations for its positioning in cancer immunotherapy.

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Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

Section: Tigit Structure Expression and Ligandsmentioning

confidence: 99%

Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

Section: Tigit's Role In Anti-cancer Immunitymentioning

confidence: 99%

See 2 more Smart Citations

TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

et al. 2021

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“…Radiotherapy has been shown to enhance immunogenicity of tumors through various mechanisms of immune modulation and therefore combination of ICIs and RT is being evaluated as an approach for HCC to take advantage of the synergistic effect [142]. TIGIT is enriched in PD1 high CD8 + TILs of HCC patients, and this subset represents the most dysfunctional and exhausted CD8 + TIL phenotype and dual blockade of TIGIT and PD-1 improved the cytotoxic potential of CD8 + TIL in HCC patients [143]. The above results indicate that combinatorial strategies are more efficacious than CPI monotherapy and new therapeutic approaches are underway to determine whether the addition of tyrosine kinase inhibition, the anti-vascular endothelial growth factor antibody bevacizumab, or additional immune CPIs can augment the proportion of patients with response to PD-1 or PD-L1 inhibition.…”

Section: T Cells-based Immunotherapy Of Hccmentioning

confidence: 99%

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

Kalathil

Thanavala

2021

Cells

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Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches 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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TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Cited by 59 publications

References 50 publications

TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

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

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