Shaping of NK cell responses by the tumor microenvironment

Abstract

Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokine-producing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.

Fig. 1

NK cell activating and inhibitory receptors and their downstream signaling molecules. Signaling pathways downstream of activating NK cell receptors typically lead to NK cell cytotoxic responses and/or cytokine production. Central molecules involved in NK cell activation are often downregulated in the tumor microenvironment. These molecules include: CD3ζ, an adaptor molecule coupled to several activating receptors; contains an immunoreceptor tyrosine-based activation motif (ITAM) that becomes phosphorylated by Src family kinases upon engagement of activating receptor(s) by its ligands; Lck kinase that phosphorylates ITAMs of CD3ζ and FcεRIγ adaptor molecules; Syk kinase that is recruited to phosphorylated ITAMs and mediates downstream signaling; additional downstream molecules such as Vav, PI3K or PLCγ. Inhibitory NK cell receptors contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) and recruit phosphatases such as SHP-1 and SHIP upon ligand recognition. These events lead to the dephosphorylation of active components downstream of activating receptors counteracting NK cell activation. Tumor-associated NK cells often upregulate expression of inhibitory receptors that result in an enhanced threshold for NK cell activation. The network was generated using the Ingenuity Pathway Analysis (IPA) software (Ingenuity Systems, www.ingenuity.com)

Fig. 2

Components of the tumor microenvironment that inhibit NK cell effector functions. Cells with suppressive function that are recruited and/or expanded in the tumor tissue such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), immature dendritic cells (iDCs) and tumor-associated macrophages (TAMs) interact with NK cells within the tumor tissue and can suppress NK cell effector function. The activation of NK cell cytotoxic responses and cytokine production can prevent the accumulation of immunosuppressive cells, e.g. by elimination of iDCs and monocytic MDSCs or by IFN-γ-mediated M1-polarization of TAMs. Soluble factors released by tumor cells as well as by infiltrating immune cells, such as soluble HLA-G (sHLA-G), soluble NKG2D ligands (sNKG2D-Ls), TGF-β, PGE2, the tryptophan-degrading enzyme, IDO, and its product kynurenine can inhibit NK cells by direct engagement of inhibitory receptors or by downregulation of activating NK cell receptors