Quantifying the contribution of transcription factor activity, mutations and microRNAs to CD274 expression in cancer patients

Bruns, Imke B.; Beltman, Joost B.

doi:10.1038/s41598-022-08356-0

Cited by 7 publications

(7 citation statements)

References 74 publications

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“…Both PD-L1 and EMT scores have been proposed as biomarkers for selecting patients responding to PD-1/PD-L1 blockade therapy ( 36 , 37 ). However, the numerous mechanisms and factors affecting the expression of PD-L1 and EMT regulators, such as ZEB1, complicate their use as selective biomarkers ( 6 , 38 , 39 ). Regarding PD-L1, our model indeed predicts that a low expression may be attributed to a lack of an active immune response (initial PD-L1 level in Figure 4B ).…”

Section: Discussionmentioning

confidence: 99%

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status

Lems,

Burger,

Beltman

2023

Front. Immunol.

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Epithelial-mesenchymal transition (EMT) and immune resistance mediated by Programmed Death-Ligand 1 (PD-L1) upregulation are established drivers of tumor progression. Their bi-directional crosstalk has been proposed to facilitate tumor immunoevasion, yet the impact of immunosuppression and spatial heterogeneity on the interplay between these processes remains to be characterized. Here we study the role of these factors using mathematical and spatial models. We first designed models incorporating immunosuppressive effects on T cells mediated via PD-L1 and the EMT-inducing cytokine Transforming Growth Factor beta (TGFβ). Our models predict that PD-L1-mediated immunosuppression merely reduces the difference in PD-L1 levels between EMT states, while TGFβ-mediated suppression also causes PD-L1 expression to correlate negatively with TGFβ within each EMT phenotype. We subsequently embedded the models in multi-scale spatial simulations to explicitly describe heterogeneity in cytokine levels and intratumoral heterogeneity. Our multi-scale models show that Interferon gamma (IFNγ)-induced partial EMT of a tumor cell subpopulation can provide some, albeit limited protection to bystander tumor cells. Moreover, our simulations show that the true relationship between EMT status and PD-L1 expression may be hidden at the population level, highlighting the importance of studying EMT and PD-L1 status at the single-cell level. Our findings deepen the understanding of the interactions between EMT and the immune response, which is crucial for developing novel diagnostics and therapeutics for cancer patients.

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Section: Discussionmentioning

confidence: 99%

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status

Lems,

Burger,

Beltman

2023

Front. Immunol.

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“…The results reported here may have diagnostic and therapeutic implications. PD-L1 has been proposed as a biomarker to predict the efficacy of PD-1/PD-L1 blockade therapy [ 70 ], yet the multi-factorial mechanisms underlying PD-L1 membrane expression complicate its use as an exclusive biomarker [ 71 , 72 ]. For example, oncogene-driven PD-L1 expression caused by EMT is constitutive, diffuse and distinct from inflammation-driven PD-L1 expression, which may occur more focally and during a limited time window.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFN γ -induced PD-L1 expression promotes tumour progression

et al. 2022

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Epithelial–mesenchymal transition (EMT) and immunoevasion through upregulation of programmed death-ligand 1 (PD-L1) are important drivers of cancer progression. While EMT has been proposed to facilitate PD-L1-mediated immunosuppression, molecular mechanisms of their interaction remain obscure. Here, we provide insight into these mechanisms by proposing a mathematical model that describes the crosstalk between EMT and interferon gamma (IFN γ )-induced PD-L1 expression. Our model shows that via interaction with microRNA-200 (miR-200), the multi-stability of the EMT regulatory circuit is mirrored in PD-L1 levels, which are further amplified by IFN γ stimulation. This IFN γ -mediated effect is most prominent for cells in a fully mesenchymal state and less strong for those in an epithelial or partially mesenchymal state. In addition, bidirectional crosstalk between miR-200 and PD-L1 implies that IFN γ stimulation allows cells to undergo EMT for lower amounts of inducing signal, and the presence of IFN γ accelerates EMT and decelerates mesenchymal–epithelial transition (MET). Overall, our model agrees with published findings and provides insight into possible mechanisms behind EMT-mediated immune evasion, and primary, adaptive, or acquired resistance to immunotherapy. Our model can be used as a starting point to explore additional crosstalk mechanisms, as an improved understanding of these mechanisms is indispensable for developing better diagnostic and therapeutic options for cancer patients.

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“…And could knowledge about the mechanisms of its upregulation help define the transition from precancer to cancer? Of all the suspected transcriptional regulators of CD274 [ 147 ], a main regulator appears to be IRF1 [ 148 ]. Indeed, loss of IRF1 expression in vitro in cancer cell lines results in a significant reduction of CD274 expression [ 149 ].…”

Section: Immune Checkpoint Markersmentioning

confidence: 99%

Precancerous Lesions of the Head and Neck Region and Their Stromal Aberrations: Piecemeal Data

Harris

Andl

2023

Cancers

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Head and neck squamous cell carcinomas (HNSCCs) develop through a series of precancerous stages from a pool of potentially malignant disorders (PMDs). Although we understand the genetic changes that lead to HNSCC, our understanding of the role of the stroma in the progression from precancer to cancer is limited. The stroma is the primary battleground between the forces that prevent and promote cancer growth. Targeting the stroma has yielded promising cancer therapies. However, the stroma at the precancerous stage of HNSCCs is poorly defined, and we may miss opportunities for chemopreventive interventions. PMDs already exhibit many features of the HNSCC stroma, such as inflammation, neovascularization, and immune suppression. Still, they do not induce cancer-associated fibroblasts or destroy the basal lamina, the stroma’s initial structure. Our review aims to summarize the current understanding of the transition from precancer to cancer stroma and how this knowledge can reveal opportunities and limitations for diagnostic, prognostic, and therapeutic decisions to benefit patients. We will discuss what may be needed to fulfill the promise of the precancerous stroma as a target to prevent progression to cancer.

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Quantifying the contribution of transcription factor activity, mutations and microRNAs to CD274 expression in cancer patients

Cited by 7 publications

References 74 publications

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status

Tumor-mediated immunosuppression and cytokine spreading affects the relation between EMT and PD-L1 status

Bidirectional crosstalk between epithelial–mesenchymal plasticity and IFN γ -induced PD-L1 expression promotes tumour progression

Precancerous Lesions of the Head and Neck Region and Their Stromal Aberrations: Piecemeal Data

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