Overview of immune-cell subsets and clinical applications in preventing metastasis
| Cell Subset | Primary tumor:Pro- metastatic | Primary tumor:Anti-metastatic | In the circulation:Pro- metastatic | In the circulation:Anti- metastatic | Metastatic niche:Pro- metastatic | Metastatic niche:Anti- metastatic | Clinical applications |
|---|---|---|---|---|---|---|---|
| CD8+ T cells | – | Recognize and kill cancer cells prior to dissemination. | – | Recognize and kill disseminated cancer cells. | – | Recognize and kill cancer cells upon entry into the metastatic niche. | Stimulation of CD8+ T cells:- Vaccination- Engineering the T cell receptor (TCR) or chimeric antigen receptor (CAR); while this is a promising way to target the primary tumor, it remains to be seen to what extent they also control metastatic cells, which may have altered antigenic properties. |
| Tregs | Immuno-suppression through TGF-β and IL-10 secretion, inhibiting cytotoxic T cell and NK cell responses. | – | Could deplete or suppress circulating T cells and NK cells to improve survival of circulating metastatic cells. [133, 134] | – | – | – | Inhibition of Tregs:- PI3K-Akt inhibitors [102]- FOXP3 inhibitors [103]Treg inhibition in mice can lead to autoimmune disease, necessitating caution or targeted, local Treg depletion (as opposed to systemic depletion) |
| NK cells | – | Recognize and kill cancer cells prior to dissemination. | – | Recognize and kill disseminated cancer cells. | Mature NK cells have fewer killing capacity. Therefore, niches with mature or exhausted NK cells are more prone to promote metastatic outgrowth. | Immature NK cells (CD27+ CD11b−) prevent metastatic niche formation. | Stimulation of NK cells: Adoptive transfer [120] or cytokines such as IL-2, IL-15, IL-21 [135]Clinical benefit, and the advantage over T cells that no priming is needed. Combinations of stimulating NK cell function and blocking NK cell inhibition by Tregs or platelet-mediated shedding could improve NK cell-mediated prevention of metastasis. |
| Macrophages | Angiogenesis- Immuno-suppression- Promote tumor cell migration and intravasation | Direct tumor cell killing, antigen presentation to T cells. | Shedding of metastatic tumor cells from the immune system. | Immuno-stimulation: produce IL-12, IL-6 and CXCL9 to stimulate the immune system. Express iNOS to kill tumor cells directly through production of nitric oxide. | Site-specific metastasis by preparing the metastic niche through induction of local immune-suppressive environment. | Local immune-stimulation | Inhibition of macrophages:- CSF-1 inhibition to inhibit infiltration in the primary tumor.- Influence polarization to favor M1 over M2, e.g. with TLR agonists [121]Caution must be taken to selectively inhibit M2 macrophages while preserving or enhancing M1 macrophage activity. |