PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway

Mirzaei, Reza; Gordon, Ashley; Zemp, Franz J.; Kumar, Mehul; Sarkar, Susobhan; Luchman, H. Artee; Bellail, Anita C.; Hao, Chunhai; Mahoney, Douglas J.; Dunn, J. Lawrence; Bose, Pinaki; Yong, V. Wee

doi:10.1126/sciadv.abh2148

Cited by 21 publications

(21 citation statements)

References 61 publications

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“…Within the University of Calgary BTIC Core, these lines were cultured chronologically, preserved, and verified. Identification of the three human BTIC lines (BT048, BT53M and BT073) has been reported previously 37 .…”

Section: Methodsmentioning

confidence: 86%

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Single cell spatial analysis identifies regulators of brain tumor initiating cells

Mirzaei

D’Mello

Liu

et al. 2022

Preprint

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Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.

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Section: Methodsmentioning

confidence: 86%

“…Identification of the three human BTIC lines (BT048, BT53M and BT073) has been reported previously 37 .…”

Section: Generation Of Gbm Patient Derived Bticsmentioning

confidence: 86%

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Mirzaei

D’Mello

Liu

et al. 2022

Preprint

Self Cite

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“…In contrast, non-canonical PD-1 signaling has been demonstrated in cancer cells, resulting in both protumor and tumor-suppressing effects [19]. Protumor effects of intrinsic PD-1 have been shown through multiple mechanisms including enhanced mTOR signaling and NFκB activation in some tumors and may even act indepently of PD-1/PD-L1 ligation [20][21][22][23]. On the contrary, in vitro and in vivo PDCD1 knockdown models, as well as immunodeficient mice inoculated with lung cancer cell lines and treated with anti-PD-1, showed increased colony expansion and tumor growth [15,24], mediated through upregulated AKT and ERK signaling [15].…”

Section: Discussionmentioning

confidence: 99%

Hematologic malignancies following immune checkpoint inhibition for solid tumors

Eijs

Wagen

Mous

et al. 2022

Cancer Immunol Immunother

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Immune checkpoint inhibition (ICI) can induce durable responses in patients with advanced malignancies. Three cases of hematological neoplasia following ICI for solid tumors have been reported to date. We present five patients treated at our tertiary referral center between 2017 and 2021 who developed chronic myeloid leukemia (two patients), acute myeloid leukemia, myelodysplastic syndrome and chronic eosinophilic leukemia during or after anti-PD-1-based treatment. Molecular analyses were performed on pre-ICI samples to identify baseline variants in myeloid genes. We hypothesize that PD-1 blockade might accelerate progression to overt myeloid malignancies and discuss potential underlying mechanisms.

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“…MDR in tumors is complex and multifactorial, including biological barrier formed by the tumor microenvironment (TME) [48][49][50][51][52][53] and overexpression of drug efflux transporter resulting in the inability to accumulate drugs intracellularly [40,[54][55][56][57] , the drug inactivation due to the specific environment of gene control and metabolism, the resistance to apoptosis and deoxyribonucleic acid (DNA) damage repair [58][59][60][61][62][63] , and immune evasion [64][65][66][67][68][69][70][71] , as shown in Figure 1.…”

Section: Mechanisms Of Tumor Resistancementioning

confidence: 99%

“…Joung et al revealed that four genes, programmed death-ligand 1 (PD-L1), MCL-1, JunB proto-oncogene (JUNB), and β1,3-Nacetylglucosaminyltransferases (B3GNT2), affect the interaction of cancer cells with T cells, conferring resistance to T cell cytotoxicity [64] . Programmed cell death protein 1 (PD-1) on the T cells interacts with PD-L1 on the cancer cells to inhibit activation of T cells [67] . To address this problem, Topalian et al proposed neoadjuvant PD-(L)1 blockade therapy to enhance systemic immunity against tumors and prevent recurrence [Figure 1D] [69] .…”

Section: Immune Evasionmentioning

confidence: 99%

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

Wang¹,

Shi²,

Yang³

et al. 2022

Cancer Drug Resist

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Cancer is one of the most harmful diseases in the world, which causes huge numbers of deaths every year. Many drugs have been developed to treat tumors. However, drug resistance usually develops after a period of time, which greatly weakens the therapeutic effect. Tumor drug resistance is characterized by blocking the action of anticancer drugs, resisting apoptosis and DNA repair, and evading immune recognition. To tackle tumor drug resistance, many engineered drug delivery systems (DDS) have been developed. Metal-organic frameworks (MOFs) are one kind of emerging and promising nanocarriers for DDS with high surface area and abundant active sites that make the functionalization simpler and more efficient. These features enable MOFs to achieve advantages easily towards other materials. In this review, we highlight the main mechanisms of tumor drug resistance and the characteristics of MOFs. The applications and opportunities of MOF-based DDS to overcome tumor drug resistance are also discussed, shedding light on the future development of MOFs to address tumor drug resistance.

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PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway

Abstract: PD-1 on glioblastoma cells promotes brain tumor growth, and therapeutic antibodies cannot suppress its proliferative effects.

Cited by 21 publications

References 61 publications

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Hematologic malignancies following immune checkpoint inhibition for solid tumors

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

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