15th Annual Symposium
Physics of Cancer
Leipzig, Germany
Sept. 30 - Oct. 2, 2024
Invited Talk
Understanding the link between immune evasion and metastasis: A story of stromal - immune cell interactions in tumor-draining lymph nodes
Greta Mattavelli1, Moutaz Helal1, Anna Frank1, Emily Riemer1, Saskia-Laureen Herbert2, Tanja Schlaiß2, Kilian Mielert3, Andreas Rosenwald3, Achim Wöckel2, Angela Riedel1
1Mildred Scheel Early Career Centre (MSNZ) for Cancer Research Würzburg, University Hospital Würzburg, Würzburg, Germany
2Department of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany
3Institute of Pathology, University of Würzburg, Würzburg, Germany
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Introduction: Immune checkpoint blockade (ICB) targeting PD/L-1 has recently been approved for triple-negative breast cancer (TNBC), but response rates are variable and independent of primary tumor PD-L1 expression. Emerging evidence suggests that tumor-draining lymph nodes (TDLNs) play a critical role in the response to ICB therapy. Furthermore, TDLN involvement is a major determinant of the occurrence of distant metastasis. In the steady state, however, LNs are responsible for effective immune responses, which are initiated upon well-organized cellular networks. How these cellular networks are reorganized to support cancer metastasis and TDLN-mediated immune evasion, via the PD/L-1 axis, remains unclear.

Material and method: We combined human patient samples and several TNBC mouse models with state-of-the-art technologies, such as single-cell and spatial transcriptomics, multi-color flowcytometry, proteomics and in vitro models.

Results and discussion: We show critical data, on how myeloid cells, in particularly monocytes, increase in TNBC-draining lymph nodes and have immunosuppressive capacity. We further show how this immunosuppressive niche is established using our TNBC mouse models and tumors with varying metastatic potential. Single cell- and spatial transcriptomic and functional data indicate that TDLN fibroblasts recruit monocytes that preferentially home to and colocalize with fibroblast-rich niches in a CCL2/ CCL7 - CCR2 axis-dependent manner. These monocytes accumulate and exhibit suppressive capacity via the T cell inhibitory molecules PD-L1 and iNOS. Proteomic analysis of tumors and TDLN interstitial fluids and in vitro studies suggested that the factor inducing Ccl2/ Ccl7 expression in TDLN fibroblasts is a TLR4 ligand. Using a signature of just three of these TLR4 ligands in patient primary tumor samples, including TNC, S100A9 and LMNA, a subset of TNBC patients with significantly worse survival was identified. Most strikingly, local inhibition – targeted at the TDLN site - of the monocyte recruitment axis, either via Ccr2 or Tlr4 antagonism, in combination with anti-PD-1 inhibition resulted in reduced LN and distant metastasis in mouse models.

Conclusion: Our results suggest a novel mechanism by which metastatic TNBC tumors reprogram the TDLN niche to support immune evasion via PD-L1, which precedes and promotes metastasis. By identifying this mechanism, we open opportunities for improving the efficacy of ICB in TNBC patients.
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