Immune determinants of the pre-metastatic niche

Abstract

Primary tumors actively and specifically prime pre-metastatic niches (PMNs), the future sites of organotropic metastasis, preparing these distant microenvironments for disseminated tumor cell arrival. While initial studies of the PMN focused on extracellular matrix alterations and stromal reprogramming, it is increasingly clear that the far-reaching effects of tumors are in great part achieved through systemic and local PMN immunosuppression. Here, we discuss recent advances in our understanding of the tumor immune microenvironment and provide a comprehensive overview of the immune determinants of the PMN's spatiotemporal evolution. Moreover, we depict the PMN immune landscape, based on functional pre-clinical studies as well as mounting clinical evidence, and the dynamic, reciprocal crosstalk with systemic changes imposed by cancer progression. Finally, we outline emerging therapeutic approaches that alter the dynamics of the interactions driving PMN formation and reverse immunosuppression programs in the PMN ensuring early anti-tumor immune responses.

Figure 1.. Pre-metastatic niche formation.

Primary tumors secrete soluble factors, such as cytokines, chemokines, hormones, and metabolites as well as extracellular vesicles and particles (EVPs) which disseminate systemically, reprogramming distant organ microenvironments. Primary tumor-derived factors exert both direct effects, via tumor-derived secreted factors (TDSFs) and EVPs circulating through the hematogenous and lymphatic systems to distant future sites of metastasis and indirect effects, mediated through their impact on non-metastatic organs that then influence host physiology. The indirect factors promote the mobilization of bone-marrow-derived cells (BMDCs), secretion of metabolites by the gut microbiome, and of stress hormones following hypothalamic-pituitary-adrenal (HPA) axis activation. The direct factors alter distant microenvironments by affecting the tissue resident cells, such as endothelial cells and fibroblasts, leading to vascular leakiness and extracellular matrix (ECM) remodeling while the indirect effects induce the recruitment of non-resident immune cells. Together, these changes generate an immunosuppressive and inflammatory environment which includes myeloid-derived suppressor cells (MDSC) BMDCs, such as VEGFR1⁺ HPCs and CD11b⁺ myeloid cells, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), T regulatory (Treg) and B regulatory (Breg) cells, γδT cells, dysfunctional dendritic cells (DCs) and natural killer (NK) cells, suppressed CD4⁺/CD8⁺ T cells, and cancer-associated fibroblasts (CAFs). The reprogrammed microenvironment then attracts disseminated tumor cells to home and colonize this permissive soil. The most common PMN sites studied to date are the LN, lung, liver, omentum, bone, and brain.

Figure 2.. Pre-metastatic niche evolution.

Tumor-derived factors such as TDSF, pro-angiogenic, pro-inflammatory factors, and EVPs trigger the formation of an early PMN characterized by ECM remodeling and inflammatory changes that reprogram the tissue-resident immune and stromal cells in distant organs that orchestrate the PMN initiation. The mid PMN, is characterized by increased fibronectin deposition and upregulation of tenascin C, enhance ECM deposition and remodeling and vascular permeability that facilitates BMDCs recruitment. In the late PMN, local secretion of inflammatory and chemotactic molecules reinforce the continued recruitment of hematopoietic progenitor cells and immature myeloid cells, neutrophils, macrophages, Tregs, and dysfunctional DCs and NK cells that crosstalk with the PMN resident cells to maintain an inflammatory and immunosuppressive circuitry. The resulting ECM modifications accompanied by enhanced immune cell recruitment, persistent inflammation, and immunosuppression support CTC adhesion and extravasation, and CTC outgrowth in the Metastatic niche.

Figure 3.. Therapeutic strategies to target the PMN and associated immunosuppression.

Direct interference with innate immunity-mediated PMN formation (purple) includes platelet targeting, blocking of myeloid cell recruitment, trafficking or docking at the PMN site, TAM re-education, MDSC depletion, and NET formation. Direct interference with adaptive immunity-mediated PMN formation (green) employs immune checkpoint blockade molecules on T and NK cells, as well as specific blockade of Tregs. Reversal of PMN immunosuppression by co-opting the anti-tumor immunity (blue) include the use of engineered MDSCs, normalization of the NK cell pool, and the use of cancer vaccines to enhance long-term CD8⁺ T cell immune responses. Therapies indirectly targeting immunity (black) that result in reduced immune evasion and boost immunotherapies include the normalization of vascular permeability, targeting pro-metastatic effects of CAFs in the PMN, targeting cancer innervation, co-opting the gut microbiome to exert anti-metastatic immunomodulation, and EV-based therapies.