A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis

Abstract

Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology.

Figure 1:

Hypothesis of natural killer (NK) cell subset differentiation and functions in decidual and tumoral tissues. NK precursors are generated in the bone marrow [1] and undergo several steps toward maturation into the major peripheral blood (PB) NK cell subsets [2]. The main PB subsets are the CD56^dimCD16⁺ [3] (90%–95% of circulating NK cells) and CD56^brightCD16^dim/- NK cells [4](5–10% of circulating NK cells) associated with lower cytotoxic activity and production of IFNγ and other cytokines, expressing the CXCR3 and CCR7 chemokine receptors. These cells [2] also appear to be a precursor to the cytotoxic CD56^dim/+CD16^+/bright NK [3], showing high levels of perforin and granzyme and expression of CX3CR1, CXCR1 and CXCR2. The developing decidua contain high levels of dNK [5] cells that are recruited into this tissue. Within the decidua (shown as a pink area) trophoblast cells release transforming growth factor (TGFβ) and express HLA-G molecules associated with reduction of NK cytotoxicity and promotion of pro-angiogenic activity [6]. The dNK [5] cells express CX3CR1, CXCR3 and CXCR4, and secrete angiogenic factors including VEGF, PlGF, CXCL8, CXCL12. Within many tumor microenvironments (shown as a grey area), tumor cells can express HLA-G and produce TGFβ along with hypoxia [7]. These elements have been associated with conversion of PB NK [3] cells into poorly cytolytic dNK-like tumor infiltrating natural killer cells (TINKs) cells able to release vascular endothelial (VEGF), placental (PlGF) growth factors and IL8 (CXCL-8) [8], thus sustaining angiogenesis [9]. It is not clear if tumor associated natural killer cells (TANKs) [10] are the result of emigration of TINKs [8] from the tumor microenvironment or due to systemic effects on NK cells of cancer-related products.

Figure 2:

NK-DC cross-talk in both normal and tumor microenvironment contexts. Natural killer (NK) cell editing of dendritic cells (DCs) plays a crucial role in the regulation of both innate and adaptive immunity. In normal tissues (light blue area), plasmacytoid [1] and classical myeloid [2] DCs can activate NK cells via the release of several cytokines [3]. Activated NK cells can edit DCs, either inducing their maturation [4] or eliminating the immature, allegedly tolerogenic [5] DCs (iDCs). NK cells also release IFNγ [6] and can eliminate cancer stem cells (CSCs)[7]. In the normal context/microenvironment, NK cells sustain Th1 polarization, necessary for an effective adaptive immune response against tumors [8]. In the tumor microenvironment (grey area) NK cells are characterized by poor cytotoxicity [9], leading to iDC accumulation [10], block of cytolytic T cell responses [11] and inducing immune tolerance of tumor cells.

Figure 3:

Involvement of TINKs in therapeutic approaches. Tumor infiltrating natural killer cells (TINKs) [1] are characterized by a substantial pro-angiogenic subset able to produce vascular endothelial (VEGF), placental (PlGF) growth factors and IL8 (CXCL-8). Several strategies to revert the “normal” anti-tumor activity are indicated: The cytotoxic activity [2] in response to activating receptors (AR) and tumor necrosis factors (TNFs) and interferon γ (IFNγ) production [3] of perforin-low (Perf^low) TINKs [1] could be restored by exposure to IL-2, IL-15 and/or IL-12, leading to a Perf^high phenotype. Because these cytokines [3] also induce up-regulation of Fc receptor γRIII (CD16) [4], antibody-dependent cell cytotoxicity (ADCC) could be restored [5] by association of IL-2/-15/-12 with monoclonal antibody (Mabs) therapeutic approaches [5]. Cytokine treated CD56^dim TINKs [6] could regain the ability of dendritic cell (DC) editing [7], leading to a Th1 polarization [8] and promotion of an adaptive anti-tumor response [9]. In addition, chemotherapy, alone or in association with IL-2 and/or IL-12 [10] could be used to functionally switch TINKs [1] to an anti-tumor phenotype by down-regulating pro-angiogenic factors (VEGF^low, PlGF^low, IL-8^low) and promoting production of IFNs and TNFs [3].