Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes

Huinen, Zowi R.; Huijbers, Elisabeth J. M.; Beijnum, Judy R. van; Nowak-Śliwińska, Patrycja; Griffioen, Arjan W.

doi:10.1038/s41571-021-00496-y

Cited by 206 publications

(177 citation statements)

References 208 publications

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“…Therefore, PVAP and other anti-angiogenic combinations may serve as possible primers of immunostimulatory therapies [ 88 ]. This is in line with our recently published observation that endothelial cell anergy (co-)determines the immune escape of tumors and angiostatic compounds can overcome this phenomenon [ 6 ].…”

Section: Discussionsupporting

confidence: 91%

“…As a result, the patients with those cold tumors, e.g., colorectal or pancreatic cancer, remain unresponsive to immunotherapies [ 5 ]. This could be due to endothelial cell anergy that (co-)determines the immune escape of tumors and angiostatic compounds [ 6 , 7 ]. Therefore, there is an unmet need to define these interactions at the molecular level, and develop therapeutic strategies to enhance tumor recognition and invasion by the immune system.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

Rausch

Blanc

Silva

et al. 2021

Cancers

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Two-dimensional cell culture-based platforms are easy and reproducible, however, they do not resemble the heterotypic cell-cell interactions or the complex tumor microenvironment. These parameters influence the treatment response and the cancer cell fate. Platforms to study the efficacy of anti-cancer treatments and their impact on the tumor microenvironment are currently being developed. In this study, we established robust, reproducible, and easy-to-use short-term spheroid cultures to mimic clear cell renal cell carcinoma (ccRCC). These 3D co-cultures included human endothelial cells, fibroblasts, immune cell subsets, and ccRCC cell lines, both parental and sunitinib-resistant. During spheroid formation, cells induce the production and secretion of the extracellular matrix. We monitored immune cell infiltration, surface protein expression, and the response to a treatment showing that the immune cells infiltrated the spheroid co-cultures within 6 h. Treatment with an optimized drug combination or the small molecule-based targeted drug sunitinib increased immune cell infiltration significantly. Assessing the therapeutic potential of this drug combination in this platform, we revealed that the expression of PD-L1 increased in 3D co-cultures. The cost- and time-effective establishment of our 3D co-culture model and its application as a pre-clinical drug screening platform can facilitate the treatment validation and clinical translation.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

Rausch

Blanc

Silva

et al. 2021

Cancers

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“…HCA on Nanostring Pancancer Immune Panel Genes 26 (Fig S5E-F) indicates presence of four phenotypes of which P7, P14 and P17 (RCM Vasc mod/high ) were found to have comparatively lower expression of immune genes as compared to P5, P6, P21, P23, P36 (RCM Inf high ). These results suggested Inf high may have more inflamed phenotypic attributes while Vasc mod/high phenotype were associated with lower immune densities and immune activation in presence of high vessels and/or trafficking, suggestive of endothelial anergy 18 . After successfully verifying tumor phenotypes on RCM and gene expression datasets, we also investigated tumor phenotyping on 3 GEO datasets 27-29 using PCA and differential gene expression analysis (DGEA) towards analyzing similar phenotypic trends in additional diverse cohorts (Fig S5).…”

Section: Resultsmentioning

confidence: 89%

“…In addition, tumor vasculature can display decreased expression of adhesion molecules, and non-responsiveness to inflammatory cytokines-attributes of vascular endothelial anergy. By downregulating trafficking of effector immune cells, endothelial anergy contributes to ineffective anti-tumor immune responses and immune evasion [20][21][22] .…”

Section: Mainmentioning

confidence: 99%

Cellular-level phenotyping of tumor-immune microenvironment (TiME) in patients in vivo reveals distinct inflammation and endothelial anergy signatures

Sahu

Tembo

Kose

et al. 2021

Preprint

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Immunotherapies, especially immune checkpoint blockade therapy have shown unprecedented clinical benefits in several malignancies, however, responses are variable emphasizing the need for effective biomarkers for patient stratification1. Phenotyping of tumors into hot, altered, or cold2 based on T-lymphocyte infiltration in tumor biopsies fails to explain and/or predict response to immunotherapy seen in a subset of patients3,4. One of the primary reasons for this suboptimal prediction by a single immune marker could be attributed to the fact that additional mechanisms within the tumor microenvironment modulate anti-tumor immunity and outcomes, including dynamic events such as tumor-angiogenesis and leukocyte trafficking2,5,6. We report novel tumor phenotypes through non-invasive spatially-resolved cellular-level analysis of the tumor immune microenvironment (TiME) and major determinants of anti-tumor immunity. Using skin cancers as a model and optical imaging using reflectance confocal microscopy (RCM)7, we determined four major phenotypes based on unsupervised clustering for relative prevalence of vasculature (Vasc) and inflammation (Inf) features: VaschighInfhigh, VaschighInflow, VasclowInf(intratumoral)high and VascmodInflow. The VaschighInfhigh phenotype correlate with high immune and vascular signatures while VaschighInflow with endothelial anergy. Automated quantification of TiME features demonstrates moderate accuracy and high correlation with corresponding gene expression. Prospective testing of TiME features prior to topical immunotherapy response shows highest response in the VasclowInf(IT)high phenotype, and revealing the added value of vascular features in predicting treatment response. This novel in vivo phenotyping combining dynamic immune and vascular features has the potential to advance fundamental understanding of the highly dynamic TiME, identify novel druggable pathways and develop robust predictors for immunotherapy outcomes.

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“…Moreover, the dysfunctional tumor vasculature can play a crucial role in immune evasion by cancer cells using an angiogenesis-induced endothelial immune cell barrier hampering antitumor immunity. It was thus suggested that exposure to pro-angiogenic factors leads to endothelial cell anergy, reduced upregulation of endothelial adhesion molecules, and thus decreased leukocyte adhesion, extravasation, and immune infiltration [100][101][102]. Hence, vessel normalization and immune modulation by angiogenic inhibitors exhibit synergistic effects that can potentiate cancer immunity and the anti-tumor response of ICI [103][104][105].…”

Section: Potential Of Anti-angiogenic Immunotherapy In CM Treatmentmentioning

confidence: 99%

Advances in Targeting Cutaneous Melanoma

Kasakovski

Skrygan

Gambichler

et al. 2021

Cancers

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To date, the skin remains the most common cancer site among Caucasians in the western world. The complex, layered structure of human skin harbors a heterogenous population of specialized cells. Each cell type residing in the skin potentially gives rise to a variety of cancers, including non-melanoma skin cancer, sarcoma, and cutaneous melanoma. Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time. The intricacy of melanoma thus necessitates diverse and patient-centered targeted treatment options. In addition to classical treatment through surgical intervention and radio- or chemotherapy, several systemic and intratumoral immunomodulators, pharmacological agents (e.g., targeted therapies), and oncolytic viruses are trialed or have been recently approved. Moreover, utilizing combinations of immune checkpoint blockade with targeted, oncolytic, or anti-angiogenic approaches for patients with advanced disease progression are promising approaches currently under pre-clinical and clinical investigation. In this review, we summarize the current ‘state-of-the-art’ as well as discuss emerging agents and regimens in cutaneous melanoma treatment.

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Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes

Cited by 206 publications

References 208 publications

Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

Characterization of Renal Cell Carcinoma Heterotypic 3D Co-Cultures with Immune Cell Subsets

Cellular-level phenotyping of tumor-immune microenvironment (TiME) in patients in vivo reveals distinct inflammation and endothelial anergy signatures

Advances in Targeting Cutaneous Melanoma

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