Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration

Ding, Lijuan; Wang, Nanya; Wang, Qiang; Fan, Xiaohui; Xin, Yuning; Wang, Shudong

doi:10.1038/s41420-023-01392-3

Cited by 11 publications

(8 citation statements)

References 48 publications

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“…These results were in line with a recent report that alveolar macrophages accumulate close to tumor cells early during tumor formation to promote epithelial-mesenchymal transition and invasiveness in tumor cells, also induce a potent suppressive Treg response 21 . We also found the expression level of immune suppressive modulators MDK and LGALS9 were upregulated in PC4, indicating an immune suppression phenotype (Figure 5J) [46][47][48] . Spatial analysis of immune cell types and states of leading edge of tumor regions reveals a local suppressive immune environment involved in promoting cancer cell invasion.…”

Section: Phenotypic Clusters From Heterogeneous Malignant Cells Are A...mentioning

confidence: 70%

Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression

Chen,

Peng,

et al. 2023

Preprint

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Spatial cellular organization patterns (COPs) in tumor microenvironment influence the tumor progression and therapeutic response, however, little is known about the cellular composition and functional potential of these multicellular structures during lung adenocarcinoma progression. Here, we integrate spatial transcriptomics with single cell RNA sequencing to characterize the local tumor and immunological landscape of samples from 8 patients with early-stage lung adenocarcinoma at different pathological stages. We identified ten COPs that show distinct associations with local immune states and clinical outcomes, including survival and therapy response. The local infiltration levels of regulatory and dysfunctional immune cells are increased with pathological progression. Cell-to-cell interactions between malignant cells and tumor microenvironment (TME) cells were involved in protumor immune state remodeling. Finally, we detected a group of malignant cells that were specifically located at the tumor boundary, representing a more aggressive state, were involved in the invasion of invasive adenocarcinoma (IAC). Altogether, these results can improve our understanding of the local microenvironment characteristics that underlie LUAD progression and may facilitate the identification of drug targets to prevent invasive progression and biomarkers for diagnosis.

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Section: Phenotypic Clusters From Heterogeneous Malignant Cells Are A...mentioning

confidence: 70%

Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression

Chen,

Peng,

et al. 2023

Preprint

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“…However, the immunosuppressive cytokine IL-10 produced by DCs can inhibit immune activation and lead to immune tolerance, facilitating viral persistence. Additionally, DCs can interact with other immune cells, such as NK cells and regulatory T cells (Tregs), influencing their activity and contributing to the delicate balance between immune control and tolerance[ 44 , 45 ]. Further research is necessary to investigate the mechanisms underlying DC impairment resulting from HBV reactivation.…”

Section: Possible Immunological Mechanisms Of Hbv Reactivationmentioning

confidence: 99%

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

Ma,

Yan,

et al. 2024

World J Gastroenterol

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Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation’s delicate balance, spanning innate and adaptive immunity. Viral factors’ disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation’s impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

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“…Nf1-/- SCs overexpress pleiotropin and midkine, homologous ligands that bind to receptor tyrosine kinases, serve as potent mitogens for neurofibroma derived cells [ 59 ], and are known to increase in response to inflammation and NF-κB-dependent signaling [ 60 ]. Evidence suggests that midkine may also stimulate inflammatory responses and promote the recruitment of multiple immune cell types, including T cells, B cells, and macrophages, to the tumor microenvironment [ 61 , 62 , 63 , 64 ]. PNF arising in Dhh-Cre;Nf1 flox/flox mice exhibit increased immune cell infiltration and dynamic changes in immune cell proportions over time [ 60 ].…”

Section: Neurofibromin Governs Sc–immune Cell Interactionsmentioning

confidence: 99%

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

White,

Rhodes

2024

Cancers

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Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)—benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.

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Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration

Cited by 11 publications

References 48 publications

Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression

Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

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