Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis

Karl, Katharina; Schütz, Birgit; Fritsch, Stephanie Deborah; Schörghofer, David; Linke, Monika; Sukhbaatar, Nyamdelger; Matschinger, Julia M.; Unterleuthner, Daniela; Hirtl, Martin; Lang, Michaela; Herac, Merima; Spittler, Andreas; Bergthaler, Andréas; Schabbauer, Gernot; Bergmann, Michael; Dolznig, Helmut; Hengstschläger, Markus; Magnuson, Mark A.; Mikula, Mario; Weichhart, Thomas

doi:10.1172/jci.insight.124164

Cited by 22 publications

(16 citation statements)

References 65 publications

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“…4a and 4b). The expression of CD11c and CD68 is similar to lung resident alveolar macrophages but they lack the characteristic CD206 expression 27,28,29 , and their accumulation at the tumour edge (interface domain) and some expression of pS6 suggests these might be reactive M1 polarized macrophages 30,31 . This macrophage subset remained fairly stable between the two treatment groups, with respect to phenotype and localisation (Fig.…”

Section: Macrophages Subsets Exhibit Different Tissue Localisation and Treatment Responsesmentioning

confidence: 99%

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Maldegem

Valand

Cole

et al. 2021

Preprint

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Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), novel highly multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimised and validated image segmentation strategies and automated the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. Incorporating user-specific plugins, imcyto can be flexibly tailored to a wide range of segmentation needs. With these methods we interrogated the dramatic remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, showcasing their potential as key discovery tools to enhance understanding of the interplay between tumour, stroma, and immune cells in the spatial context of the tissue.

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Section: Macrophages Subsets Exhibit Different Tissue Localisation and Treatment Responsesmentioning

confidence: 99%

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Maldegem

Valand

Cole

et al. 2021

Preprint

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“… 41 Interestingly, MTORC2 activity was not detected in primary human and mouse CRC samples, but was found to be expressed in macrophages where it contributed to anti-tumor activity. 42 …”

Section: Current Biomarker-based Stratification Of Mcrcmentioning

confidence: 99%

“…41 Interestingly, MTORC2 activity was not detected in primary human and mouse CRC samples, but was found to be expressed in macrophages where it contributed to antitumor activity. 42 A number of factors other than KRAS/NRAS and BRAF mutations influence the efficacy of anti-EGFR therapy, including plasma levels of EGFR ligands such as amphiregulin (AREG) and epiregulin (EREG), 43 and these may be monitored to provide an indication of resistance to anti-EGFR therapy. 24 EGFR gene copy number and acquired mutations in extracellular domains also may contribute anti-EGFR therapy resistance in mCRC.…”

Section: Current Biomarker-based Stratification Of Mcrcmentioning

confidence: 99%

Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

Gmeiner¹

2021

OTT

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Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy although considerable progress has resulted from characterizing molecular alterations such as RAS mutation status and extent of microsatellite instability (MSI) to guide optimal use of available therapies. The availability of gene expression profiling, next generation sequencing technologies, proteomics analysis and other technologies provides high resolution information on individual tumors, including metastatic lesions to better define intra-tumor and inter-tumor heterogeneity. Recent literature applying this information to further customize personalized therapies is reviewed. Current biomarker-based stratification used to select optimal therapy that is personalized to the mutation profile of individual tumors is described. Recent literature using whole exome sequencing of metastatic lesions and primary CRC tumors and other advanced technologies to more fully elucidate the tumor biology specific to mCRC sub-types and to develop more precise therapies that improve outcomes is also reviewed.

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“…For example, mTOR signaling plays a complex role in regulating NK cell function whereby mTORC1 signaling stimulates NK cell cytolytic function, whereas mTORC2 activity favors immunosuppressive NK cells [ 189 ]. Finally, mTORC2 deletion in macrophages stimulates a pro-inflammatory microenvironment that potentiates colitis-induced colon cancer [ 190 ]. These studies suggest that rapalogs (mTORC1-specific) and active site dual-specificity mTOR inhibitors (asTORi) may differentially impact the tumor immune microenvironment and, potentially, sensitivity to combination immunotherapies.…”

Section: Kinase Inhibitors Target Immune Cells In the Tumor Micromentioning

confidence: 99%

Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors

Ahn

Ursini‐Siegel

2021

IJMS

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Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.

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Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis

Cited by 22 publications

References 65 publications

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors

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