Inducible CCR2+ nonclassical monocytes mediate the regression of cancer metastasis

Area of Science:

• Immunology
• Cancer Biology
• Cellular Trafficking

Background:

• Immunotherapy resistance is a major challenge in cancer treatment, often driven by cancer-induced suppression of immune responses.
• Cancer cells utilize CCL2 (chemokine C-C motif ligand 2) to recruit CCR2 (C-C chemokine receptor type 2)-expressing classical monocytes, promoting metastasis and immune evasion.
• CCR2-expressing classical monocytes can differentiate into intravascular nonclassical monocytes with anti-cancer properties, but they struggle to reach tumor sites.

Purpose of the Study:

• To investigate a distinct subset of CCR2-expressing nonclassical monocytes and their potential therapeutic role in overcoming immunotherapy resistance.
• To explore methods for expanding and inducing these monocytes for enhanced anti-cancer activity.

Main Methods:

• Analysis of CCR2-expressing nonclassical monocyte populations in mice and humans during inflammatory conditions (organ transplant, COVID-19).
• Induction of these monocytes in vitro using NOD2 (nucleotide-binding oligomerization domain-containing protein 2) activators on classical monocytes.
• Assessment of inducible CCR2+ nonclassical monocyte infiltration and anti-tumor efficacy in murine models of melanoma, lung, breast, and colon cancer.

Main Results:

• An underrepresented subset of CCR2+ nonclassical monocytes was expanded during inflammation and could be induced by NOD2 activation.
• These inducible CCR2+ nonclassical monocytes effectively infiltrated various tumor types in mice, reversing increased metastasis in Nod2-/- mice.
• Within tumors, these monocytes secreted CCL6 (chemokine C-C motif ligand 6) to recruit NK cells, leading to tumor regression independently of T and B cells.

Conclusions:

• Pharmacological induction of CCR2+ nonclassical monocytes represents a promising strategy for treating immunotherapy-resistant cancers.
• This approach leverages innate immune cells (NK cells) for tumor regression, offering an alternative to lymphocyte-dependent mechanisms.