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21Mar 2019

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Targeting macrophages helps chemotherapy succeed

It's the interferon that does the trick

In an online publication in Nature Cell Biology, Camilla Salvagno from Karin de Visser's group and other researchers  revealed how targeting intratumoral macrophages enhances the efficacy of platinum-based chemotherapy in a preclinical mouse model for breast cancer.

Mechanistically, it is not the disappearance of the macrophages itself that does the trick. The targeting of macrophages stimulates intratumoral type I interferon signaling, which improves the tumor response to cisplatin. The researchers successfully validated the increased type I interferon signaling upon macrophage inhibition in biopsies derived from cancer patients.

Further elimination of immunosuppressive neutrophils in the preclinical breast cancer model enhanced the efficacy of chemotherapy even more, by unleashing an anti-tumor immune response.

These findings highlight the complex regulatory roles of macrophages and neutrophils during chemotherapy response and may contribute to the design of optimal combination therapies with macrophage-targeting drugs.

The immune system and cancer

Ideally, our immune system fights cancer - CD8+ T cells are a case in point -  but frequently immune cells help cancer survive and metastasize. For instance, recent studies revealed that tumor-associated macrophages and neutrophils, which are often the most abundant immune cells in tumors, limit the efficacy of chemotherapy.

Bottleneck for a rational combination therapy

Recently, compounds have been developed that target tumor-associated macrophages. However, the mechanisms underlying therapeutic benefit are still poorly understood and it is unknown which chemotherapeutic drugs can be best combined with these macrophage-targeting compounds. This presents a bottleneck for treating patients with a rationally designed combination therapy.

Look for the mechanisms!

In an online publication in Nature Cell Biology, Camilla Salvagno from Karin de Visser's group and other researchers now show how important it is to dive into the cellular and intercellular mechanisms within the complex tumor environment.


Targeting Macrophages to enhance platinum-based chemo

Type I interferon response

They discovered that targeting macrophages in a transgenic mouse model for breast cancer by blocking the colony-stimulating factor-1 (CSF-1) receptor enhances the anti-cancer efficacy of platinum-based chemotherapy in an indirect way. It is not the absence of macrophages that does the trick but rather a type I interferon response within the tumor, triggered by blocking the CSF-1 receptor. The finding that blockade of CSF-1R increases intratumoral type I interferon signaling was successfully validated in tumor biopsies derived from patients.

Only platinum-based chemotherapy

Interestingly, the targeting of macrophages enhanced the therapeutic benefit of platinum-based chemotherapeutics, but not taxane-based chemotherapeutics, illustrating that the use of macrophage-targeting compounds requires careful matching with chemotherapeutic drugs.

Step 2: targeting neutrophils

The researchers also found that neutrophils limited the therapeutic benefit of cisplatin and CSF-1R blockade by inhibiting anti-tumor immune responses. They discovered that the elimination of neutrophils with an anti-Ly6G antibody further increased tumor response to cisplatin and anti-CSF-1R treatment by unleashing anti-tumor immunity.

Camilla Salvango et al., 'Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response', Nature Cell Biology, Published online 18 March 2019  Corresponding author: Karin de Visser


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