Locally sourced: site-specific immune barriers to metastasis

Abstract

Tumour cells migrate very early from primary sites to distant sites, and yet metastases often take years to manifest themselves clinically or never even surface within a patient's lifetime. This pause in cancer progression emphasizes the existence of barriers that constrain the growth of disseminated tumour cells (DTCs) at distant sites. Although the nature of these barriers to metastasis might include DTC-intrinsic traits, recent studies have established that the local microenvironment also controls the formation of metastases. In this Perspective, I discuss how site-specific differences of the immune system might be a major selective growth restraint on DTCs, and argue that harnessing tissue immunity will be essential for the next stage in immunotherapy development that reliably prevents the establishment of metastases.

Fig. 1. Tissue immunity determines metastatic progression.

Before metastases manifest themselves clinically, tumour cells need to overcome multiple barriers throughout their journey from the primary site until they successfully colonize a distant site. First, they invade locally and intravasate the endothelium to enter the circulation, where they travel alone or in clusters with other cells, in search of a new site to extravasate and expand. The few disseminated tumour cells (DTCs) that survive the journey then face attrition from the specific immune environment within the distant site: where antimetastatic tissue-resident immune cell populations are dominant, DTCs blend into the physiological context and persist in a quiescent state for several years or even decades (dormancy stage of cancer); conversely, microenvironments depleted of antimetastatic immune cells or enriched in other immune cells conducive to DTC reactivation support metastatic outgrowth into clinically detectable metastases. Treating the specific immune microenvironment at distant sites may be a way to effectively control DTCs. DC, dendritic cell; ILC, innate lymphoid cell; NK, natural killer.

Fig. 2. Site-specific differences of the immune system contribute to differential emergence of metastases within and across common metastatic sites.

The immune system is customized by anatomical site, featuring distinct cell types that are distributed at defined ratios and spatial locations, where they engage in dynamic interactions with diverse non-immune resident cells to constantly safeguard tissue homeostasis. It is the product of these interactions that sets the immune tone for recognition of disseminated tumour cells (DTCs), and makes an ideal locale for DTCs to either be kept dormant or establish metastases within and across different sites. a, In the liver, DTCs migrate from the portal triad vessels to the sinusoid and into the subendothelial space of Disse, where they encounter immune and non-immune resident cells, all positioned in compliance with liver zonation. Liver-resident natural killer (NK) cells (or liver group 1 innate lymphoid cells (ILC1s)) are the main immune gatekeepers of DTC dormancy, whereas activation of hepatic stellate cells precipitates metastasis through suppression of liver-resident NK cell expansion or recruitment of immunosuppressive populations. b, In the lungs, NK cells and T cells are the major immune barriers to metastasis, and their function is countered by diverse immunosuppressive populations, including ILC2s, neutrophils, monocytes, regulatory T cells (T_reg cells) and γδ T cells. Tissue-resident macrophages and activated fibroblasts feed the recruitment of these immunosuppressive populations by maintaining a hospitable inflammatory milieu permissive of metastasis. c, The bone is the primary niche for haematopoietic stem cells (HSCs), and is co-opted by DTCs to remain dormant. NK cells and T cells actively survey this niche, in concert with ILC2s that preserve the bone integrity through suppression of bone-resorbing osteoclasts. Conversely, an imbalance towards osteoclast differentiation supports the cycle of bone destruction that triggers dormant DTC reactivation and metastasis initiation. Other awakening factors in the bone include the accumulation of neutrophils, monocytes and T_reg cells, as well as enhanced innervation. d, Access to the brain parenchyma is restricted by the blood–brain barrier (BBB), and thus DTC extravasation to the brain takes longer than in other tissues. Once in the brain, DTCs park tightly at the perivasculature, and are actively surveyed and often eliminated by NK cells and T cells, with the latter helped by ILC2-mediated enhanced antigen presentation by dendritic cells (DCs). Microglia, the main immune cell residents of the brain, act in a context-dependent manner, being either suppressive of or permissive of metastatic outgrowth. NKT cell, natural killer T cell.

Fig. 3. Diversity and spatial distribution of tissue immunity may underlie the resistance to disseminated tumour cell outgrowth at infrequent sites of metastases.

a, In the thyroid, the continuous production and high concentration of thyroid hormones (such as tri-iodothyronine, thyroxine and calcitonin) maintains natural killer (NK) cell, T cell and NKT cell activity, stimulates the maturation and antigen presentation capacity of dendritic cells (DCs), and sparks monocyte phagocytic activity. It is plausible that this naturally hyperactive local immunosurveillance maintains dormancy of disseminated tumour cells (DTCs) and antagonizes metastatic outgrowth at this site. b, Beyond their high numbers, splenic immune cells display an intricate positioning within the three main structures of the spleen: the inner white pulp (WP), where cytokine-mediated compartmentalization separates T cell and B cell areas into distinct zones; the red pulp (RP), which harbours many immune cells with innate immune functions that selectively express distinct pattern recognition receptors, helping to tailor the nature of both the early innate immune response and the subsequent adaptive immune response; and the in-between marginal zone, harbouring concentric macrophage subsets and DCs with defined positioning to ensure efficient pathogen encounter and antigen presentation. It is possible that this sharp anatomical parsing of immunosurveillance readies the splenic antimetastatic niche by facilitating low-probability DTC–immune cell interactions. Although these hypotheses are enticing, specific mechanisms driving immune-mediated low frequency of metastases in the thyroid and spleen remain to be seen.