A new therapy targets the many tumors resistant to the "revolution of immunotherapy".

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The majority of patients still do not respond to immune checkpoint treatments.

This type of treatment had been presented as revolutionary a few years ago. Unfortunately, medical research has accustomed us to these shattering announcements that never materialize. A subtype of macrophages, a form of immune cells with anti-inflammatory properties, protects rather than destroys cancer cells. Instead of directly attacking cancer cells, a new immunotherapy technique targets and removes this subtype of macrophages, after which the immune system begins to reduce cancer.

Tumor-associated macrophages

Tumor-associated macrophages are the most abundant immune cells present in solid tumors, and the fact that they contribute significantly to tumor progression is well documented.

In addition to their trophic functions favoring angiogenesis, invasion, and metastasis, tumor-associated macrophages may inhibit proliferation and activation of T-cells by various mechanisms.

Bad clinical results, but not everywhere

The important functions of macrophages in relation to tumor progression have led to a substantial interest in the development of new therapeutic strategies for targeting tumor-associated macrophages.

However, despite a strong correlation between tumor-associated macrophage accumulation and poor clinical trial results, in some cases the accumulation of macrophage subsets associated with specific tumors may be associated with a good prognosis.

An example is the frequency of HLA-DR + tumor-associated macrophages, which has been associated with beneficial effects in several studies (de Vos van Steenwijk et al., 2013, Ino et al., 2013), perhaps reflecting the role of macrophages in orchestrating protective immune responses (Mantovani and Allavena, 2015).

In fact, recent studies using a coupled monocell analysis by mass cytometry and RNA sequencing have revealed an unprecedented level of diversity within the tumor-associated macrophage compartment in patients with lung adenocarcinoma and cell carcinoma kidney (Chevrier et al., 2017; Lavin et al., 2017). In the case of renal cell carcinoma, 17 different tumors-associated macrophage phenotypes have been documented (Chevrier et al., 2017).

Diversity of tumor-associated macrophage subsets

Researchers still lack basic knowledge about the functions of different subsets of tumor-associated macrophages and their respective contributions to tumor progression.

However, it is tempting to think that selective targeting of tumor-associated macrophage subsets with protumoral functions, while preserving the immune functions of other tumor-associated macrophage subsets, could offer significant clinical benefits .

CD163 protein as a marker of bad proostic

The expression of CD163 by tumor-associated macrophages has been shown to be a particularly potent indicator of poor prognosis in several human cancers (Komohara et al., 2014), including melanoma (Jensen et al., 2009; Bronkhorst et al. al., 2011; Lee). et al., 2018).

CD163 is a macrophage and monocyte-specific transmembrane protein that acts as a receptor for haptoglobin-hemoglobin complexes formed during intravascular hemolysis (Kristiansen et al., 2001). Hemoglobin is contained in red blood cells or red blood cells. In case of destruction of the latter (physiologically or not), the hemoglobin-haptoglobin complex is removed from the plasma mainly at the level of the spleen.

CD163 expression is induced by tumor-promoting cytokines such as IL-6 and IL-10, whereas inflammatory stimuli, including LPS, TNFα, and IFNγ, result in rapid expression regulation. and removal of the CD163 membrane via proteolytic excretion (Etzerodt et al., 2010; Etzerodt and Moestrup, 2013).

This, combined with the generation of heme anti-inflammatory metabolites from hemoglobin scavenging, has led to the association of CD163 + macrophages with anti-inflammatory functions (Etzerodt and Moestrup, 2013).

Caution is needed

Indeed, the link between CD163 accumulation and tumor-associated macrophages and tumor progression is based exclusively on correlations with clinical evolution, and experimental evidence of specific promotion functions. the tumor are still missing.

Moreover, the recent development of immune check point inhibitors (immune control point), such as anti-PD-1, has had a huge impact on the treatment of cancer, particularly in malignant melanoma (Robert and al., 2015; Ugurel et al., 2017). The blocking of PD-1 / PD-L1 signaling has resulted in unprecedented tumor regression rates (Tumeh et al., 2014), but only for a small number of patients.

New therapeutic strategies

Therefore, new therapeutic strategies to enhance antitumor immunity, to overcome immune checkpoint resistance or to improve serious adverse side effects, are absolutely necessary.

Researchers conducted extensive characterization of tumor-associated macrophage subsets in a clinically relevant mouse model of melanoma resistant to anti-PD-1 treatment.

The researchers show that the specific targeting of a minor subset of macrophages associated with tumors expressing CD163 is sufficient to induce tumor regression in this model.

It is important to note that the specific macrophage depletion associated with CD163 + tumors results in increased recruitment of effector T cells and CCR2-dependent inflammatory monocytes, both of which contribute to tumor regression.

These studies are the first to demonstrate the selective targeting of macrophages associated with tumors and CD163 and their specific contribution to tumor progression.

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