Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Galletti, G; Scielzo, Cristina; Barbaglio, Federica; Rodriguez, Tania Veliz; Riba, Michela; Lazarevic, Dejan; Cittaro, Davide; Simonetti, Giorgia; Ranghetti, Pamela; Scarfò, Lydia; Ponzoni, Maurilio; Rocchi, Martina; Corti, Angelo; Anselmo, Achille; Rooijen, Nico van; Klein, Christian; Ries, Carola H.; Ghia, Paolo; Palma, Michele De; Caligaris-Cappio, Federico; Bertilaccio, Maria Teresa Sabrina

doi:10.1016/j.celrep.2016.01.042

Cited by 94 publications

(93 citation statements)

References 47 publications

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“…The number of differentially expressed genes used for analysis is indicated. Data are presented as pseudo‐heatmap with magnitudes of activation Z ‐scores color‐coded as indicated in the legend; all non‐gray comparisons are –log 10 ( P ‐value) > 2.5 unless otherwise indicated. Gene set enrichment analysis (GSEA) was performed to compare transcriptomes of genotype comparisons (wt/Act vs. wt/wt; HPV8/Act vs. HPV8/wt; HPV8/Act vs. wt/wt, [all]/Act vs. [all]/wt) to three published datasets of tumor‐associated macrophages (TAM) (Ojalvo et al , ; Franklin et al , ; Galletti et al , ). Gene sets are composed of top genes upregulated (TAM UP) or downregulated (TAM DOWN) in TAM vs. normal tissue macrophages.…”

Section: Resultsmentioning

confidence: 99%

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Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

et al. 2016

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Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2‐positive monocytes. Gene expression profiling of macrophages from pre‐tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor‐associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody‐mediated depletion of macrophages, which strongly suppressed activin‐induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation.

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Section: Resultsmentioning

confidence: 99%

“…wt/ wt, [all]/Act vs. [all]/wt) to three published datasets of tumor-associated macrophages (TAM)(Ojalvo et al, 2009;Franklin et al, 2014;Galletti et al, 2016). Gene sets are composed of top genes upregulated (TAM UP) or downregulated (TAM DOWN) in TAM vs. normal tissue macrophages.…”

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confidence: 99%

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

et al. 2016

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“…43). Although quizartinib is primarily considered to be a FLT3 inhibitor, it is also a potent inhibitor of CSF1R, a target recently implicated for CLL treatment because of its effects on supportive nurse-like monocyte/macrophage cells that express CSF1R (44)(45)(46), highlighting the importance of teasing out tumor-intrinsic mechanisms from tumor-extrinsic microenvironment contributions to sensitivity/resistance. Accordingly, simultaneous inhibition of BTK-and CSF1R-mediated signaling pathways may result in further improvement of responses (Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Kurtz

Eide

Kaempf

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

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“…CL is currently used in immune research and clinical trials to eliminate macrophages and phagocytes in multiple malignancies. For example, TAM depletion with CL impaired tumor engraftment, reduced tumor growth, and favored mouse survival in a chronic lymphocytic leukemia model (30). However, despite its effective tumor regression effects, it also induced severe side effects such as sensitivity toward infections and weight loss in mice and patients (31–34).…”

Section: Targeting Tams With Chemotherapy or Immunotherapymentioning

confidence: 99%

Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

2017

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Tumor-associated macrophages (TAMs) play a central role in tumor progression, metastasis, and recurrence after treatment. Macrophage plasticity and diversity allow their classification along a M1–M2 polarization axis. Tumor-associated macrophages usually display a M2-like phenotype, associated with pro-tumoral features whereas M1 macrophages exert antitumor functions. Targeting the reprogramming of TAMs toward M1-like macrophages would thus be an efficient way to promote tumor regression. This can be achieved through therapies including chemotherapy, immunotherapy, and radiotherapy (RT). In this review, we first describe how chemo- and immunotherapies can target TAMs and, second, we detail how RT modifies macrophage phenotype and present the molecular pathways that may be involved. The identification of irradiation dose inducing macrophage reprogramming and of the underlying mechanisms could lead to the design of novel therapeutic strategies and improve synergy in combined treatments.

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Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Cited by 94 publications

References 47 publications

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

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