Table 1 Overview of immune-cell subsets and clinical applications in preventing metastasis

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.