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Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8⁺ T Cell Response in Hepatocellular Carcinoma.

ABSTRACT: Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host's antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8⁺ T cells is discussed in this review.

SUBMITTER: Pena-Asensio J

PROVIDER: S-EPMC8073815 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsThe mechanism underlying resistance to immunotherapy involves engagement of immune checkpoint pathways. The transcriptional and epigenetic processes of checkpoint molecules, however, have not been well investigated. We thus studied whether the transcription factor myeloid zinc finger 1 (MZF1) may promote resistance to immunotherapy in hepatocellular carcinoma (HCC).MethodsSingle-cell RNA-sequencing was performed to study the correlation between MZF1 and tumour microenvironment features in six patients with HCC. Combined immunohistochemistry and multi-immunofluorescence analyses were performed for verification. Ectopic expression of MZF1 was used in both orthotopic and genetically engineered hydrodynamic mouse HCC models for in vivo experiments. Proteome analysis, including protein degradation assays, ubiquitination assays, and co-immunoprecipitation assays, revealed the function of MZF1 in immune checkpoint pathways.ResultsSingle-cell RNA-sequencing suggested an immunosuppressive environment and a strong correlation with the immune checkpoint programmed death ligand 1 (PD-L1) in MZF1-overexpressing tumours. Analyses of 163 HCC samples demonstrated that MZF1 expression in HCC cells is associated with decreased T-cell infiltration. In vivo experiments showed that ectopic MZF1 expression in HCC cells impairs T-cell recruitment, resulting in resistance to immune checkpoint blockade. Mechanistically, MZF1 accelerated PD-L1 ubiquitination by binding to the cyclin-dependent kinase 4 (CDK4) activation site, while a direct bond between CDK4 and MZF1 led to increased MZF1 expression.ConclusionsMZF1 promotes PD-L1 ubiquitination via CDK4 and possibly MZF1. Inhibition of CDK4 can therefore restore PD-L1 expression and may be a potential strategy for combination with anti-PD-L1 antibodies.Impact and implicationsResistance to immune checkpoint blockade with anti-programmed death ligand 1 (PD-L1) antibody therapy is attributed to oncogenic alterations of tumour cells, however, effective countermeasures are yet to be established. Here, we report that the transcription factor myeloid zinc finger 1 (MZF1) can bind to the cyclin-dependent kinase 4 (CDK4) activation site and accelerate PD-L1 ubiquitination. A CDK4 inhibitor therefore enhances anti-PD-L1 antibody efficacy by blocking MZF1 signalling. This indicates a potential benefit of combining CDK4 inhibitors and anti-PD-L1 antibodies for the treatment of advanced HCC.

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Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8⁺ T Cell Response in Hepatocellular Carcinoma.

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Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma.

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Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8⁺ T Cell Response in Hepatocellular Carcinoma.