Myeloid cells are the most abundant leukocyte population in solid tumors. In contrast to the heterogeneity found in tumoral macrophages (tM𝜑s), the diversity of short-lived lineages such as neutrophils (Neu), monocytes (Mo) and their progenitors, is only starting to be appreciated. Interestingly, growing evidence suggests that epigenetic reprogramming of myeloid cells upon exogenous or endogenous insults leads to an altered response to subsequent triggers, which can favor disease progression. These changes occur through chromatin remodeling and gene-expression alterations, a process known as trained immunity. Given that myeloid cell activity can control remotely the physiology of peripheral organs, the goal of this project is to determine whether myeloid cells in metastatic sites are co-opted by signals raised in primary tumors. While myeloid cell accumulation in tumors is a hallmark of poor prognosis, it is uncertain whether tumor cells hijack innate immune cells in metastatic organs, thereby contributing to tumor expansion and therapy resistance.

The development of metastases in triple-negative breast cancer (TBNC) represents a highly complex and poorly understood process. It is therefore of significant interest to examine myeloid responses in treatment-naïve patients and upon checkpoint blockade (ICB) in order to identify combinatory strategies that harness biological programs to favor anti-tumor immunity. Therefore, we hypothesize that remote training of myeloid cells is induced by primary tumors promoting metastasis tolerance and expansion. By dissecting the myeloid composition of early metastatic TNBC tumors using a combination of lineage-tracing approaches and single-cell RNA-sequencing (scRNAseq), we aim to identify the network of myeloid vulnerabilities to target metastasis.