Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-L1 antibodies

Borch, Troels Holz; Donia, Marco; Andersen, Mads Hald; Svane, Inge Marie

doi:10.1016/j.drudis.2015.07.003

Cited by 32 publications

(20 citation statements)

References 86 publications

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“…In this study, we found that despite the continuous proliferation of T cells in tumor-DLN of lymphopenic mice, the cytotoxicity of tumor reactive CD8 + T cells rapidly decline over time. To Exhausted effector T cells can be effectively activated by anti-PD-1 antibody, but they were taken into exhausted state quickly by other immunosuppressive signals in tumor microenvironment [21,22]. In this study, we found that new microenvironment after immune reconstitution can enhance the therapeutic effects of anti-PD-1 antibody treatment.…”

Section: Discussionmentioning

confidence: 79%

PD-1/PD-L1 axis suppressed homeostatic proliferation–driven antitumor immunity during recovery from lymphopenic condition.

Yang¹,

Liu²,

Lai³

et al. 2020

Preprint

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Background Lymphopenic condition after radiotherapy or chemotherapy might be able to create an environment to mount an efficient antitumor immunity through the homeostatic proliferation of residual or adoptive lymphocytes. However, the antitumor immunity seems to decrease rapidly with the growth of tumor, and the mechanism remain elusive. Methods In this study, we first examined the dynamic change of PD-1 expression on T cells and analyzed the connection between PD-1 expression and the exhaustion of CTLs when the number of T cells recovered from lymphopenic conditions. Anti-PD-1/PD-L1 therapies, including anti-PD-1 antibodies, PD-1 or PD-L1 knockout by Crispr-Cas9 system, were used in the study to evaluate the role of PD-1/PD-L1 block on the antigen recognition, differentiation, activation, killing, survival and prognosis of HP cells. Results Our study found that in the mouse model of homeostatic proliferation, although T cells proliferated continuously in lymphopenic host, the number of IFN-γ-releasing CD8+T cells rapidly decreased in course of homeostatic proliferation, indicating the immunosuppressive state in tumor microenvironment. The expression of PD-1 on T cells, increased gradually in course of homeostatic proliferation, were significantly negatively related to the cytotoxicity of effector T cell. Blocking of PD-1/PD-L1 axis by PD-1 antibody promoted HP cells to recognize tumor associated antigen (TAAs) and resulted in the activation of DC cells. It can also enhanced the number of IFN-γ-releasing CD8+ T cells and the cytotoxicity of effector T cell in lymphopenic mice. Furthermore, PD-1 antibody induced a portion of tumor-specific CTL convert to central memory T cells (TCM). Finally, we found that Crispr/Cas9-mediated knockout of PD-1 in T cells or PD-L1 in melanoma cells significantly enhanced homeostatic proliferation–driven antitumor responses and inhibited tumor growth. Conclusion These findings suggested PD-1/PD-L1 played an important role in the formation of immune tolerance during the period of homeostatic proliferation. Anti-PD-1/PD-L1 therapies may be used to enhance antitumor immunity during recovery from lymphopenic condition after chemotherapy or radiotherapy.

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Section: Discussionmentioning

confidence: 79%

PD-1/PD-L1 axis suppressed homeostatic proliferation–driven antitumor immunity during recovery from lymphopenic condition.

Yang¹,

Liu²,

Lai³

et al. 2020

Preprint

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“…Tumor microenvironment is affected by not only chemokines but also immunological checkpoints. The expression of inhibitory immune checkpoint proteins in tumor tissue is different from that in normal tissue, showing that it is changed in tumor microenvironment [50]. Cancers evade immune response and contribute to the progression of cancer through the overexpression of inhibitory ligands [51,52].…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance and regulatory networks of DAP3 in hepatocellular carcinoma microenvironment based on bioinformatics analysis

Jiang¹,

Sun²,

Zhu³

et al. 2020

Preprint

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Background: Death-associated protein 3 (DAP3) is a GTP-binding protein in the component of the small subunit of the mitochondrial ribosome. Abnormal expression of DAP3 potentially correlates with carcinogenesis. However, the specific functions of DAP3 in hepatocellular carcinoma (HCC) are still not clarified.Methods: The expression of DAP3 in different cancer types was analyzed using TIMER and Oncomine, and DAP3 expression in HCC was detected using Oncomine, GEPIA and UALCAN. DAP3 promoter methylation was shown via MEXPRESS. The effect of DAP3 on HCC prognosis was analyzed via Kaplan-Meier plotter, GEPIA and UALCAN. Moreover, co-expressed genes with DAP3 and their regulators, kinases, miRNA and transcription factor targets were identified using LinkedOmics. Furthermore, cBioPortal was used to detect the genetic alteration of DAP3. Finally, TIMER was utilized to evaluate the correlations between DAP3 and immune cell infiltration, while the correlation between DAP3 and three immune factors was detected through TIDISB.Results: DAP3 expression was significantly high in several tumor tissues, including HCC. The promoter methylation level of DAP3 in HCC tissues was remarkably lower compared with normal tissues. Additionally, high DAP3 expression was related to overall survival (OS). Functional network analysis indicated that DAP3 regulated the translational elongation, ribonucleoprotein complex biogenesis, tRNA metabolic process and mitochondrial respiratory chain complex assembly. Moreover, DAP3 expression represented strong correlations with the immune cell infiltration and immune factors in HCC. Conclusions: Our results indicated that DAP3 acted as a potential prognostic marker in HCC, laying a groundwork for further study of DAP3 in HCC.

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“…Several potential therapeutic strategies that target immunosuppression in cancer are currently under investigation, such as the blocking of inhibitory pathways with monoclonal antibodies. 19 An alternative strategy, which we have adopted, is to utilize specific T cells to target immune suppression. 20 In the present study, when we examined the effect on immunogenicity of co-stimulating a DC-based vaccine with long peptide epitopes derived from PD-L1, we found that T cell reactivity toward the vaccine was significantly increased.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine

et al. 2016

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We recently described naturally occurring PD-L1-specific T cells that recognize PD-L1-expressing immune cells as well as malignant cells. In the present study, we investigated whether the immunogenicity of a dendritic cell (DC)-based vaccine could be influenced by co-stimulation with a known PD-L1-derived epitope. We incubated a PD-L1-derived peptide epitope (19 amino acids long) or a control peptide (an irrelevant HIV epitope) with peripheral blood mononuclear cells from patients with malignant melanoma who had received a DC-based vaccine. We observed a significantly higher number of T cells that reacted to the vaccine in cultures that had been co-stimulated with the PD-L1 peptide epitope compared to cultures incubated with control peptide. Next, we characterized a novel PD-L1-derived epitope (23 amino acids long) and found that co-stimulation with both PD-L1 epitopes boosted the immune response elicited by the DC vaccine even further. Consequently, we observed a significant increase in the number of vaccine-reacting T cells in vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate immunogenicity of DC vaccines. Addition of PD-L1 epitopes may thus be an easily applicable and attractive option to augment the effectiveness of cancer vaccines and other immunotherapeutic agents.

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Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-L1 antibodies

Cited by 32 publications

References 86 publications

PD-1/PD-L1 axis suppressed homeostatic proliferation–driven antitumor immunity during recovery from lymphopenic condition.

PD-1/PD-L1 axis suppressed homeostatic proliferation–driven antitumor immunity during recovery from lymphopenic condition.

The prognostic significance and regulatory networks of DAP3 in hepatocellular carcinoma microenvironment based on bioinformatics analysis

PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine

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