CD169(+) Macrophages in Primary Breast Tumors Associate with Tertiary Lymphoid Structures, T(regs) and a Worse Prognosis for Patients with Advanced Breast Cancer

SIMPLE SUMMARY: We here show that CD169(+) TAMs in primary breast tumors are associated with tertiary lymphoid-like structures (TLLSs), T(reg) and B(reg) signatures, and a worse prognosis for the patient. In contrast, CD169(+) TAMs and TLLSs present in lymph node metastases were associated with better prognosis. We propose that the negative prognostic value related to CD169(+) TAMs and TLLSs in primary breast tumors is a unique consequence of an immunosuppressive tumor environment in advanced breast cancers. This knowledge is important for understanding the immune landscape in breast cancer and for future targeted therapies. ABSTRACT: The presence of CD169(+) macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169(+) macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169(+) macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169(+)/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and T(reg) and B(reg) signatures. We propose that the negative prognostic value related to CD169(+) macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, T(regs) and B(regs).