Leveraging the Dynamic Immune Environment Triad in Patients with Breast Cancer: Tumour, Lymph Node, and Peripheral Blood

Abstract

During the anti-tumour response to breast cancer, the primary tumour, the peripheral blood, and the lymph nodes each play unique roles. Immunological features at each site reveal evidence of continuous immune cross-talk between them before, during and after treatment. As such, immune responses to breast cancer are found to be highly dynamic and truly systemic, integrating three distinct immune sites, complex cell-migration highways, as well as the temporal dimension of disease progression and treatment. In this review, we provide a connective summary of the dynamic immune environment triad of breast cancer. It is critical that future studies seek to establish dynamic immune profiles, constituting multiple sites, that capture the systemic immune response to breast cancer and define patient-selection parameters resulting in more significant overall responses and survival rates for breast cancer patients.

Keywords: breast cancer; lymph node; systemic immunity; triple-negative breast cancers.

Figure 1

Key interactions of the immune macroenvironment. The cancer-immunity cycle is a coordinated process involving the primary tumour, the peripheral blood, and the tumour-draining lymph node (LN), with the potential to generate effective anti-tumour immune responses. The primary tumour can either interact directly with the peripheral blood and the LN due to the dissemination of cancer cells or indirectly via the secretion of distant immunosuppressive mediators. The presence of a tumour induces hematopoietic dysregulation via increased abundances of hematopoietic stem cells (HSCs) and granulocyte monocyte progenitors (GMPs) in the bone marrow, followed by peripheral blood alterations where myeloid and lymphoid cells are increased and decreased, respectively. Tumour antigens secreted from the primary tumour can travel to the two other sites. Antigen presenting cells (APCs), e.g., macrophages and dendritic cells (DCs), which have encountered these antigens, either at the tumour lesion or in the periphery, are trafficked to the LN, where they prime and activate naïve lymphocytes. These primed effector immune cells then infiltrate the tumour to carry out effector functions or enter the circulation as memory subsets.

Figure 2

Tertiary lymphoid structures and germinal centres within the lymph node. Both tertiary lymphoid structures (TLSs) and germinal centres hold cellular and functional similarities which are associated with better prognosis in breast cancer patients. Germinal centres are dynamic immune structures within LNs which lead to the generation of affinity matured antibody-producing cells and memory B cells via strong interactions between activated B cells and T follicular helper (Tfh) cells as well as follicular dendritic cells (FDCs). The germinal centre is organised into two zones: the light zone where these intercellular interactions occur and the dark zone where selected B cells proliferate. We have found that LN-positive TNBC patients who present with more, smaller and cortically located germinal centres in their cancer-free LNs exhibit longer time to distant metastasis. Remarkably, mature TLSs within the primary tumour contain a germinal centre-like aggregate encircled by a T cell zone where macrophages and dendritic cells activate naïve T cells. TLSs are characterised by the presence of high endothelial venules (HEV). This germinal centre also leads to the generation of antibody-producing and memory B cells. TNBC patients who exhibit more histologically detected TLSs, more HEVs, and whose tumours express higher levels of TLS gene expression signatures, have better prognosis.

Figure 3

Immunostimulatory effects of chemotherapy across the immune macroenvironment. In the TME, chemotherapy results in an expansion of ICOSL+ B cells, increased TLSs and increased CD8:Treg ratios. ICOSL+ B cells accumulate in TLSs, where they may promote B cell survival in a germinal centre-like response to generate high affinity memory B and plasma cells. Chemotherapy induces immunological cell death in metastatic tumour cells migrating through the periphery and may lead to the upregulation of ICOSL+ B cells. Chemotherapy increases the CD8:Treg cell ratio in the peripheral blood and the proportion of naïve CD4+ and CD8+ T cells. Increased levels of naïve T cells and ICOSL+ B cells may migrate from the periphery to the LN, leading to enhanced activation of effector T cells and promotion of B cell survival and memory B/plasma cells. Activated effector T cells and high affinity B cells from the LN then egress back to the TME where they mediate enhanced anti-tumour activity.

Figure 4

Immunomodulatory effects of chemotherapy during treatment. (A) Within an immune-infiltrated TME, proportions of CD4+ and CD8+ T cells increase initially before falling after NACT. Post-NACT, CD4+ T cells, B cells and regulatory T cells are depleted compared to baseline levels. (B) In peripheral blood, proportions of NK cells, naïve CD4+ T cells and naïve CD8+ T cells are initially increased whilst PD-1+ CD4+ T cells with an ‘exhausted’ phenotype are depleted compared to baseline. Post-NACT, all subtypes are depleted compared to baseline levels except ‘exhausted’ CD4+ T cells which are increased compared to both baseline and on-treatment values. Immune cell subtypes are variably depleted with B cells being the most affected, followed by both CD4+ subtypes. Both CD8+ subtypes and NK cells are less affected. All subtypes recover to a degree, but B cells and CD4+ T cells remain low for longer. To date, no studies have evaluated the long-term effects of NACT on PD-1+ CD4+ T cells. (C) In cancer-free LNs, post-NACT, total lymphocytes are depleted compared to baseline levels with B cell zones being more diminished than T cell zones. Studies are warranted to evaluate the on-treatment or long-term effects of NAT on lymphocytes within the cancer-free LN.