Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion

Lan, Yan; Moustafa, Mahmoud; Knoll, Maximilian; Xu, Chunxiao; Furkel, Jennifer; Lazorchak, Adam S.; Yeung, Tsz-Lun; Hasheminasab, Sayed-Mohammad; Jenkins, Molly H.; Meister, Sarah; Yu, Huakui; Schlegel, J.; Marelli, Bo; Tang, Zheng; Qin, Guozhong; Klein, Carmen; Qi, Jin; Zhou, Cheng; Locke, George; Krunic, Damir; Derner, Melissa G; Schwager, Christian; Fontana, Rachel E.; Kriegsmann, Katharina; Jiang, Feng; Rein, Katrin; Kriegsmann, Mark; Debus, Jürgen; Lo, Kin-Ming; Abdollahi, Amir

doi:10.1016/j.ccell.2021.08.008

Cited by 124 publications

(84 citation statements)

References 48 publications

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“…The TME provides strong support for tumor cells and has been demonstrated to play pivotal roles in tumor occurrence, progression, metastasis, and the e cacy of therapeutic interventions. [31,32,33] Among the cell types in the TME, immune cells such as macrophages, natural killer cells, neutrophils, dendritic cells, and myeloid derived suppressor cells, play signi cant roles in tumor progression. [34,35,36,37,38,39,40,41,42] In this study,…”

Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Biomarker and Immune Infiltration of CDH23 in Acute Myeloid Leukemia

Yang

et al. 2021

Preprint

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Background: Cadherin-23 (CDH23), which plays an important role in intercellular adhesion, is involved in the progression of several types of cancer. However, the biological functions and impact of CDH23 expression on the prognosis of patients with acute myeloid leukemia (AML) are yet to be explored. Herein, we aim to characterize the role and molecular functions of CDH23 in AML.Methods: The expression level of CDH23 were assessed in patients with AML by Gene Expression Profiling Interactive Analysis (GEPIA). The prognostic value of CDH23 was analyzed via GEPIA and LinkedOmics. Correlation analysis and biology function analysis were conducted by LinkedOmics and GeneMANIA database. Relationship of CDH23 with immune infiltration level was detected by TIMER. Results: In the present study, aberrant overexpression of CDH23 was first confirmed in patients with AML and contributed to poor prognosis. Notably, we observed a negative correlation between CDH23 mRNA expression and immune cell infiltration by calculating the ESTIMATE score. In addition, functional enrichment analysis confirmed that CDH23 plays a crucial role in tumor immunity. Conclusions: Our findings indicate that upregulation of CDH23 expression corresponded to shortened overall survival of patients with AML. CDH23 may be involved in mediating tumor immunity, and this highlights the potential of CDH23 as a therapeutic target in AML.

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Section: Discussionmentioning

confidence: 99%

Identification of Prognostic Biomarker and Immune Infiltration of CDH23 in Acute Myeloid Leukemia

Yang

et al. 2021

Preprint

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“…More recently, Lan et al reported the development of bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of the TGFβ RII receptor to trap TGFβ, fused to a human immunoglobulin G1 antibody blocking PD-L1 [52]. Using this molecule in combination with RT in several immune-cold murine tumor models, they showed a synergic action leading to higher survival, increased TIL, reprogramming of the TME, and reduced tissue fibrosis [53]. Additionally, regression of spontaneous lung metastases was observed.…”

Section: Combination With Other Therapies 231 Targeting Molecular Modulators Of the Immune Responsementioning

confidence: 99%

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Boustani

Lecoester

Baude

et al. 2021

Cancers

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Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

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“…

In the current issue of Cancer Cell, Lan et al 1 demonstrate that a bifunctional fusion protein targeting TGF-b and PD-L1 can synergize with radiation therapy to simultaneously augment tumor control and reduce normal tissue toxicity.

DECLARATION OF INTERESTSS.F.B. owns equity in, receives compensation from, serves as a consultant for, and sits on the scientific advisory board and board of directors of Volastra Therapeutics, Inc. C.M.R.

…”

mentioning

confidence: 99%

“…In the current issue of Cancer Cell, Lan et al 1 demonstrate that a bifunctional fusion protein targeting TGF-b and PD-L1 can synergize with radiation therapy to simultaneously augment tumor control and reduce normal tissue toxicity.…”

mentioning

confidence: 99%

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Co-targeting TGF-β and PD-L1 with radiation therapy: The Goldilocks principle

Bakhoum

Rudin

2021

Cell Reports Medicine

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Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion

Cited by 124 publications

References 48 publications

Identification of Prognostic Biomarker and Immune Infiltration of CDH23 in Acute Myeloid Leukemia

Identification of Prognostic Biomarker and Immune Infiltration of CDH23 in Acute Myeloid Leukemia

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Co-targeting TGF-β and PD-L1 with radiation therapy: The Goldilocks principle

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