Immune cell promotion of metastasis

Abstract

Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells.

Figure 1. A long journey to develop metastatic tumours

Most malignant solid tumours metastasize from the primary organ to another, such as the lungs, liver, bone and brain. To establish the metastatic tumour, cancer cells undertake several steps that are known as the metastatic cascade. First, cancer cells escape from the tumoricidal immune response that is mediated by killer cells, such as CD8⁺ T cells and natural killer (NK) cells, and produce systemic factors that establish a tumour-supportive environment (pre-metastatic niche) in the future metastatic site. The tumour cells also change the microenvironment of the primary site to increase the density of blood vessels (angiogenesis), which enhances tumour cell egress from the primary site by invasion through the surrounding stroma and intrusion into blood vessels (intravasation). The circulating tumour cells are then arrested in microvessels in the metastatic site where they need to survive. At the metastatic site, the arrested tumour cells escape from the blood vessel (extravasation), survive at the metastatic niche and proliferate to form the deadly metastatic tumour.

Figure 2. Preparation for a metastatic journey

a | In the primary tumour, cancer cells secrete chemokines and cytokines to recruit tumour-associated macrophages (TAMs), tumour-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs) and regulatory T (T_Reg) cells. These cells directly suppress the cytotoxic functions of natural killer (NK) cells and CD8⁺ T cells through the production and expression of various factors, including β-galactoside-binding protein (βGBP), programmed cell death 1 ligand 1 (PDL1) and B7-H4, which increase tumour growth, invasion and egress from the primary site. Accumulation of T_Reg cells is also promoted by TAMs through the production of CC-chemokine ligand 22 (CCL22) and by regulatory B (B_Reg) cells via transforming growth factor-β (TGFβ) secretion. MDSCs secrete interleukin-6 (IL-6), IL-23 and TGFβ that recruits T helper 17 (T_H17) cells. T_H17 cells secrete IL-17, which promotes recruitment of MDSCs and the secretion of granulocyte colony-stimulating factor (G-CSF) from cancer-associated fibroblasts (CAFs) that in turn promotes immunosuppressive function of MDSCs. MDSCs are also recruited via a plasmacytoid dendritic cell (pDC)-mediated mechanism. b | The primary tumour also produces systemic factors, such as vascular endothelial growth factor A (VEGFA), TGFβ, tumour necrosis factor (TNF) and lysyl oxidase (LOX), that induce chemotactic protein expression (S100A8, S100A9 and serum amyloid A3 (SAA3)) and extracellular matrix remodelling in the metastatic sites before tumour cell arrival. These environmental changes recruit immature myeloid cells that form clusters and secrete matrix metalloproteinase 9 (MMP9) to promote subsequent outgrowth of metastasizing cancer cell. The immature myeloid cells express very late antigen 4 (VLA4) and are also recruited to the pre-metastatic niche by its ligand fibronectin. TAMs and T_Reg cells are also recruited to the pre-metastatic niche by primary tumour-derived fibrin clots, and by CCL2 and CCL22, respectively, and these cells promote future metastasis. CSF1, colony-stimulating factor 1; CXCL, CXC-chemokine ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; HMGB1, high mobility group protein B1; MIF, macrophage migration inhibitory factor; PGE2, prostaglandin E2; SEMA3A, semaphorin 3A.

Figure 3. Promotion of the first step of metastasis

a | Tumour-associated macrophages (TAMs) become pro-angiogenic through their response to colony-stimulating factor 1 (CSF1), which suppresses anti-angiogenic factor expression, and angiopoietin 2 (ANG2), which enhances their interaction with endothelial cells and promotes the vessel network formation that is necessary for haematogenous dissemination. Tumour angiogenesis is also induced by vascular endothelial growth factor A (VEGFA) and WNT7B secreted by TAMs. TAM-mediated angiogenesis helps the haematogenous dissemination of cancer cells by increasing the density of leaky blood vessels, which in turn provide CXC-chemokine ligand 2 (CXCL2) and CXCL8 that increase invasiveness of cancer cells. b | Near blood vessels, cancer cells secrete CSF1 to prompt TAMs to produce epidermal growth factor (EGF), which in turn activates EGF receptor on cancer cells and increases their invasiveness. This EGF–CSF1 loop is triggered by cancer-associated fibroblast (CAF)-derived factors, such as heregulin β1 (HRGβ1) and CXCL12. Cancer cells migrate towards blood vessels with TAMs and interact with endothelial cells, creating a tumour microenvironment for metastasis (TMEM) where the cancer cells intravasate. Several environmental factors, including interleukin-4 (IL-4) from CD4⁺ T cells or tumour cells, promote the differentiation of macrophages to tumour-promoting TAMs that engage in the EGF–CSF1 paracrine loop and produce cathepsin proteinases, CC-chemokine ligand 18 (CCL18) and the extracellular matrix (ECM) regulator osteonectin to accelerate migration and intravasation of cancer cells. Tumour-associated neutrophils (TANs) acquire their pro-tumorigenic phenotype via tumour-derived transforming growth factor-β (TGFβ) within the tumour microenvironment. Myeloid-derived suppressor cells (MDSCs) recruited by tumour-derived CXCL5 and macrophage migration inhibitory factor (MIF) also help cancer cells to enter the vessels. HMGB1, high mobility group protein B1; MMP, matrix metalloproteinase.

Figure 4. Helping to overcome the rate-limiting steps of metastasis

After leaving the primary sites, tumour cells need to survive in the circulation and following arrest at the metastatic sites. This process is helped by fibrin clot formation by platelets and survival signals delivered by them and by tumour-associated macrophages (TAMs) that activate AKT signalling via vascular cell adhesion molecule 1 (VCAM1) on tumour cells, as well as regulatory T (T_Reg) cells, through the production of receptor activator of nuclear factor-κB ligand (RANKL). At the metastatic sites, cancer cells trapped in emboli secrete CC-chemokine ligand 2 (CCL2) to recruit inflammatory monocytes towards metastatic sites, in which the inflammatory monocytes differentiate into metastasis-associated macrophages (MAMs). MAMs secrete vascular endothelial growth factor A (VEGFA) and increase vascular permeability, which promotes extravasation of cancer cells. MAMs are also involved in the survival and persistent growth of emigrated cancer cells. Cancer cell extravasation and retention at the metastatic sites are also supported by direct interactions through intercellular adhesion molecule 1 (ICAM1) with tumour-associated neutrophils (TANs), which are recruited by CXC-chemokine ligand 8 (CXCL8) that is secreted by the tumour cells. TANs also enhance the entrapment of circulating cancer cells by producing neutrophil extracellular traps (NETs). In addition, platelets increase vascular permeability following tumour extravasation by releasing ATP-containing vesicles. NK cell, natural killer cell.