Role of tissue-resident FOLR2+ Macrophages as Organizers of the Tumor Immune MicroEnvironment

Introduction

The infiltration of CD8+ T cells in tumors is crucial for the development of immunity against cancer. We have recently identified a tissue-resident macrophage population expressing the folate receptor 2 (FOLR2) and infiltrating human and murine breast tumors.

Tumor Microenvironment

We have shown that tumor-infiltrating CD8+ T cells form lymphoid aggregates around FOLR2+ macrophages in a perivascular niche. The abundance of FOLR2+ macrophages associates with lymphocyte infiltration, the onset of tertiary lymphoid structures (TLS), and favorable prognosis.

Prognostic Significance of TLS

The abundance of TLS in cancer correlates with better prognosis and clinical response to immunotherapy. Yet, the molecular and cellular cues underlying TLS formation in tumors are ill understood.

Hypothesis

Here we hypothesize that FOLR2+ macrophages locally shape the compartment of tumor-infiltrating CD8+ T cells. Mechanistically, we will address if FOLR2+ macrophages spark local CD8+ T cell responses directly, by interacting with T lymphocytes, or indirectly, by fostering TLS formation.

Methodology

To this end, we will:

1. Develop a high-dimensional analysis of the FOLR2+ macrophage-perivascular niche using tissue imaging, spatial transcriptomics, and single-cell RNA sequencing.
2. Implement a new murine genetic model developed in the lab enabling the inducible ablation of FOLR2+ macrophages and conditional gene inactivation.
3. Deliver a mechanistic analysis of cellular cross-talks involving FOLR2+ macrophages and supporting the development and maintenance of TLS.

Immunotherapy Strategies

Lastly, we will explore new immunotherapy strategies harnessing the immunogenic function of FOLR2+ macrophages purposed to induce anti-tumor CD8+ T cell responses. To this end, we will use antibody-mediated targeting of FOLR2+ macrophages to increase antigen presentation and/or innate activation.

Conclusion

This study will provide fundamental insights on how tissue-resident macrophages regulate tumor immunity and a proof of concept for macrophage subset-specific therapeutic interventions to treat cancer.