Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis

Klemm, Florian; Möckl, Aylin; Salamero-Boix, Anna; Alekseeva, Tijna; Schäffer, Alexander; Schulz, Marcel H.; Niesel, Katja; Maas, Roeltje R.; Groth, Marie; Elie, Benelita T.; Bowman, Robert L.; Hegi, Monika E.; Daniel, Roy Thomas; Zeiner, Pia S.; Zinke, Jenny; Harter, Patrick N.; Plate, Karl H.; Joyce, Johanna A.; Sevenich, Lisa

doi:10.1038/s43018-021-00254-0

Cited by 52 publications

(33 citation statements)

References 86 publications

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“…42 Importantly, a recent study reported, in a mouse model of breast-to-brain metastasis, that the inhibition of CD115 induced a compensatory increase of GM-CSF synthesis by pericytes that induced the acquisition by TAM of an inflammatory and tissue repair profile. 49 One can thus suspect that, in vivo, the neutralization of the M-CSF-IL-34/CD115 axis may exacerbate the role of GM-CSF, which would then promote the generation, in humans, of inflammatory macrophages favoring tumor recurrence.…”

Section: Differences In the Processes Of Generation And Functional Po...mentioning

confidence: 99%

Antitumor strategies targeting macrophages: the importance of considering the differences in differentiation/polarization processes between human and mouse macrophages

Monnier

Paolini

Vinatier

et al. 2022

J Immunother Cancer

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Macrophages are the immune cells that accumulate the most in the majority of established tumors and this accumulation is associated with a poor prognosis. Tumor-associated macrophages (TAMs) produce inflammatory cytokines and growth factors that promote tumor expansion and metastasis. TAMs have recently emerged as targets of choice to restore an efficient antitumor response and to limit tumor growth. Many molecules targeting TAMs are actually evaluated in clinical trials, alone or in combination. While these molecules induce tumor regression and stimulate cytotoxic responses in mouse models of tumor development, results from early clinical trials are less impressive. In this review, we list the biological differences between human and mouse macrophages that help explain the different efficacy of antitumor strategies targeting TAMs between human and animal studies. Differences in the impact of survival and polarization factors and in the cytokines produced and markers expressed as well as the limitations of extrapolations based on in vitro models of TAM-like generation should be considered in order to improve the design and efficacy of antitumor drugs targeting TAMs.

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Section: Differences In the Processes Of Generation And Functional Po...mentioning

confidence: 99%

Antitumor strategies targeting macrophages: the importance of considering the differences in differentiation/polarization processes between human and mouse macrophages

Monnier

Paolini

Vinatier

et al. 2022

J Immunother Cancer

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“…In contrast to previous findings from glioblastoma mouse models, where TAMs survived CSF1R inhibition and were instead re-educated ( 169 , 170 ), a recent work demonstrated that targeting TAMs with the CSF1R inhibitor BLZ945 delayed brain metastatic onset and led to an initial tumor response with transient stasis of established metastases ( 232 ).CSF1R inhibitors have also been evaluated in combination treatments in preclinical studies. In breast cancer models, the efficacy of paclitaxel (Taxol) was enhanced by CSF1R inhibitor–mediated TAM depletion ( 10 , 233 ).…”

Section: Macrophagesmentioning

confidence: 89%

Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils

Russo

Nastasi

2022

Front. Oncol.

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The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing the therapeutic outcome is widely accepted and appreciated. Several therapeutic strategies to modify or modulate the TME, like angiogenesis or immune checkpoint inhibitors, showed clinical efficacy and received approval from regulatory authorities. Within recent decades, new promising strategies targeting myeloid cells have been implemented in preclinical cancer models. The predominance of specific cell phenotypes in the TME has been attributed to pro- or anti-tumoral. Hence, their modulation can, in turn, alter the responses to standard-of-care treatments, making them more or less effective. Here, we summarize and discuss the current knowledge and the correlated challenges about the tumor-associated macrophages and neutrophils targeting strategies, current treatments, and future developments.

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“…With regard to this result, an inhibitor of STAT5, AC4-130, was added to BLZ945 and led to significant synergistic anti-tumor effects with reduced tumor growth. Moreover, the combination induced a morphological change of TAM and reduced neuro-inflammation [ 90 ]. Previously, we discussed the key role of G-CSF in the maturation and recruitment of proinflammatory neutrophils in BM.…”

Section: Targeting Cytokines For Treatmentmentioning

confidence: 99%

Cytokine Landscape in Central Nervous System Metastases

et al. 2022

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The central nervous system is the location of metastases in more than 40% of patients with lung cancer, breast cancer and melanoma. These metastases are associated with one of the poorest prognoses in advanced cancer patients, mainly due to the lack of effective treatments. In this review, we explore the involvement of cytokines, including interleukins and chemokines, during the development of brain and leptomeningeal metastases from the epithelial-to-mesenchymal cell transition and blood–brain barrier extravasation to the interaction between cancer cells and cells from the brain microenvironment, including astrocytes and microglia. Furthermore, the role of the gut–brain axis on cytokine release during this process will also be addressed.

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Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis

Cited by 52 publications

References 86 publications

Antitumor strategies targeting macrophages: the importance of considering the differences in differentiation/polarization processes between human and mouse macrophages

Antitumor strategies targeting macrophages: the importance of considering the differences in differentiation/polarization processes between human and mouse macrophages

Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils

Cytokine Landscape in Central Nervous System Metastases

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