Revealing the Role of Macrophage Subpopulations in Predicting Clinical Outcomes in Cancer

Tumors often contain a transcriptionally heterogenous mix of macrophages – known as tumor associated macrophages or TAMs – where their infiltration predicts poor outcomes for most types of cancer. Not surprisingly, interest in these macrophages as targets for cancer therapy has grown rapidly in recent years, especially in combination with conventional chemotherapy, radiotherapy, or immunotherapy. Monotherapies targeting TAMs, however, have shown limited evidence of anti-tumor activity.

The authors of a recent article published in Cancer Discovery suggest that the lack of efficacy observed with monotherapies may be due to the fact that these approaches monolithically repress macrophages without consideration for their heterogeneity. With this backdrop, the researchers conducted a study to comprehensively define the spatial organization of TAM subsets. They reasoned that revealing this complexity may enable improved targeting of macrophages in cancer and help better predict clinical outcomes.

For this study, the researchers leveraged Akoya’s PhenoCycler-Fusion (formerly known as CODEX) platform and applied a 36-plex panel comprised of antibodies targeting epithelial and stromal tumor compartments to breast cancer and colorectal cancer tissue microarrays. They noted that Akoya’s highly multiplexed spatial biology technology was critical to this work as “Unbiased and highly multiplexed profiling across all cell-types within a given organ, and across multiple organs, is needed to dissect the spatial organization of macrophages within a tissue, as well as cell-cell interactions that shape macrophage roles in the tumor microenvironment.”

The researchers were able to resolve five distinct human macrophage populations occupying spatially distinct niches, with discrete histological properties, and conferring distinct effects on clinical outcomes:

• IL4I1+ macrophages were present in regions exhibiting high cell turnover in
  healthy and cancerous tissues and their presence correlated with anti-PD1 treatment response in breast cancer and favorable outcomes in patients with colorectal cancer.
• SPP1+ macrophages were associated with hypoxia and tumor necrosis and predicted poor outcome in colorectal cancer patients.
• LYVE1+ and FOLR2+ macrophage populations were conserved across both breast and intestine tissues, with a subset of FOLR2+ tissue resident macrophages enriched in the plasma cell niche.
• NLRP3+ macrophages co-localize with neutrophils and activate an inflammasome in tumors.

By elucidating the landscape of discreet macrophage niches, this study provides new insights for development of precision-targeted TAM-directed immunotherapies.

Access the full study here.