Inhibiting macrophage PI3Kγ to enhance immunotherapy

Zheng, Wei; Pollard, Jeffrey W.

doi:10.1038/cr.2016.132

Cited by 24 publications

(16 citation statements)

References 9 publications

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“…Intracellular PI3Kγ has recently been suggested to be a target for immunotherapy in macrophages. PI3Kγ inhibition can switch macrophage phenotypes from immune tolerance to immune surveillance by regulating the NFκB and mTOR-C/EBP pathways 26,43 . In agreement with previous reports, our results revealed that PI3Kγ inhibition increased antitumor cytokines and decreased protumor cytokines in macrophages, thus enhancing apoptosis-related cancer cell death regardless of the TAM subtype.…”

Section: Discussionmentioning

confidence: 99%

The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

et al. 2020

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Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progressionfree survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial-mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer.

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Section: Discussionmentioning

confidence: 99%

The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

et al. 2020

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“…Aside from a deregulated function in tumor cells PI3Kγ contributes in multiple ways to tumor growth and metastasis. Some of these augmentable PI3Kγ effects may be therapeutically exploited by PI3Kγ-targeted immuno- (as already outlined, see above) or angiogenic inhibition or by targeting the effect of PI3Kγ on the fibrous stromal tissue around tumors to fight malignancies [138,201,202]. Lack of PI3Kγ in mice indicated specific roles in endothelial cells, as endothelial progenitor cells displayed reduced integration into endothelial networks required for proper capillary formation [50].…”

Section: Biological Functions Of Pi3kγmentioning

confidence: 99%

Function, Regulation and Biological Roles of PI3Kγ Variants

Nürnberg

Beer‐Hammer

2019

Biomolecules

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Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted.

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“…Many of these TAM reprogramming strategies are currently under active clinical evaluation 26 . Notably, CD40 agonists work through activating CD40L-downstream NF-kB pathway 56 , 59 ; HDAC inhibitors work through altering histone modifications 55 , 60 ; PI3Kγ inhibitors work through stimulating NF-κB activation while inhibiting C/EBPβ activation 57 , 61 ; and creatine uptake works through regulating cytokine responses 58 . Our discovery of MAO-A as a critical regulator of TAM polarization through modulating oxidative stress provides a drug target and a mechanism of action (MOA) for expanding TAM-repolarizing strategies.…”

Section: Discussionmentioning

confidence: 99%

Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy

Wang

et al. 2021

Nat Commun

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Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

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Inhibiting macrophage PI3Kγ to enhance immunotherapy

Cited by 24 publications

References 9 publications

The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

The FBW7-MCL-1 axis is key in M1 and M2 macrophage-related colon cancer cell progression: validating the immunotherapeutic value of targeting PI3Kγ

Function, Regulation and Biological Roles of PI3Kγ Variants

Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy

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