MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

Ebert, Peter; Cheung, Jeanne; Yang, Yagai; McNamara, Erin; Hong, Rebecca; Москаленко, Марина; Gould, Stephen E.; Maecker, Heather; Irving, Bryan; Kim, Jeong M.; Belvin, Marcia; Mellman, Ira

doi:10.1016/j.immuni.2016.01.024

Cited by 620 publications

(497 citation statements)

References 56 publications

(67 reference statements)

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“…Although MAPK signaling is important for early steps of T cell activation, 64,65 several studies have shown that MEK inhibitors reprogram the tumor microenvironment and potentiate responses to checkpoint immunotherapy. 66–68 In these studies, tumor growth was reduced by the combination of MEK inhibitors and various forms of immunotherapy, but tumors were not completely eradicated. It would be interesting to test whether RON and MEK inhibitors can cooperate to provide a better therapeutic outcome in the context of checkpoint immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…These findings were mechanistically explained by another study using the same model. Ebert et al [112] demonstrated that MEK inhibition profoundly blocks naive CD8 T-cell priming. At the same time, this pharmacological inhibition increases the number of antigen-specific effector CD8 T cells in the tumor and protects CD8 TILs from death driven by chronic TCR stimulation [112].…”

Section: Mek Inhibitionmentioning

confidence: 99%

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Bedognetti

Roelands

Decock

et al. 2017

Emerging Topics in Life Sciences

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Correspondence: Davide Bedognetti (dbedognetti@sidra.org)With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer.

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“…However, from serial tumor biopsy specimens of melanoma patients receiving BRAF and MEK inhibitors as well as from in vivo experiments with MEK inhibitors, it became clear that MEK inhibitors stimulate MITF and melanocyte-lineage antigen expression and augment T cell infiltration (18,24). Furthermore, MEK inhibitors have an additional antitumor immunity effect, by inhibiting the interaction between tumor cells and "M2-like" macrophages, which does not allow the entry of effector T-cells into the tumor (25,26). These effects make very appealing the combination of MEK inhibitors with ICB even for BRAF wild-type melanoma patients.…”

Section: Introductionmentioning

confidence: 99%

The combination of checkpoint immunotherapy and targeted therapy in cancer

Karachaliou¹,

Cao²,

Sosa³

et al. 2017

Ann. Transl. Med.

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Abstract:The therapeutic possibilities for patients with metastatic melanoma have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune modulating therapies that unleash the patient antitumor immunity. These therapeutic changes have impressively increased the median overall survival of the patients. Considering the dramatic but transient responses that occur with targeted therapies for a subgroup of patients and the durable responses that can be achieved with immunotherapy in a subset of patients, a lot of effort is ongoing for the clinical development of combinations of these two therapeutic approaches. Herein we discuss the existing preclinical and clinical data for the combination of targeted therapies and immunotherapy focusing mainly on melanoma and non-small cell lung cancer (NSCLC).

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MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade

Cited by 620 publications

References 56 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

The combination of checkpoint immunotherapy and targeted therapy in cancer

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