Unveiling how the molecular landscape of TNBC sculps intratumoral macrophage origin and function

ABSTRACT/PROJECT SUMMARY. Triple-negative breast cancer (TNBC) is a heterogenous set of diseases and is considered one of the most aggressive breast cancer subtypes. TNBC lack of well-defined endocrine markers limits the therapeutic options for these patients. This has spurred significant efforts towards developing

therapies directed towards the tumor microenvironment, but these have demonstrated only modest success. This is attributed to the high functional heterogeneity of macrophages, which is in part determined by their origin, and the distinct molecular landscape of different TNBC subtypes. Our overarching objective is to elucidate a

link between the molecular profile of TNBC and macrophage origin and function in order to establish the groundwork for the finetuning of the next generation of macrophage-targeted therapies to consider the tumor's molecular signature as a proxy for macrophage function. The overall objective of this proposal is to examine a

potential enrichment of macrophages from different origins and functional profiles in TNBC subtypes with divergent molecular landscapes. The central hypothesis is that luminal TNBC subtypes are enriched for tumor antagonistic TRMs and their ablation gives way to pro-tumor MDMs colonization. The rationale is that

intratumoral macrophages can stem from different origins (i.e., embryonically derived tissue-resident (TRMs) or monocyte-derived (MDMs)), which strongly influence their functional profile. MDMs are associated with tumor promoting properties, while TRMs have been reported to play tumor antagonistic roles. Our preliminary data

supports that TNBC with divergent molecular profiles are enriched for macrophages of divergent origins. This proposal consists of proof-of-principle studies to demonstrate macrophages TNBC molecular subtypes that preserve epithelial properties are enriched for tumor antagonistic TRMs, while TNBC molecular subtypes that

have acquired mesenchymal features are enriched for tumor-promoting MDMs. Along this trajectory, the central hypothesis will be tested by pursuing two specific aims. Aim 1 will determine the origin and function of intratumoral macrophages in claudin-low and luminal-like TNBC tumor subtypes and the need for epithelial

features to main a TRM pool. Aim 2 will determine a skewing of the macrophage compartment towards pro- tumor MDMs in luminal-like TNBC after cessation of macrophage-ablation therapy. The proposed studies are innovative because they will establish a correlation between TNBC molecular profile and macrophage origin and

function. The project is significant because establishing the molecular landscape of TNBC as a proxy for macrophage function will serve to tailor macrophage-targeted therapies to account for macrophage heterogeneity.