NK cells sense tumors, course of disease and treatments: Consequences for NK-based therapies

Abstract

The recent findings on NK activation indicate that these cells are important antitumor effectors. NK cells participate in the graft-vs.-leukemia effect to control the relapse in leukemic patients transplanted with allogeneic hematopoietic stem cells. In various tumors, correlation between NK cell infiltrates and prognosis were reported. However, tumor-infiltrating NK cells are yet poorly characterized. We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell-based therapies.

Figure 1. Regulation of NK cell activation. (A) Main NK receptors (lower line) and respective ligands on target cells (upper line) implicated in NK cell triggering and inhibition. (B) Functions of NK cells (cytotoxicity and cytokine secretion) depend on a balance between opposing signals derived from activating and inhibitory receptors. The presence and density of ligands dictate whether the target cell will be susceptible (immune surveillance) or not (self tolerance) to NK cell lysis.

Figure 2. Tumors parameters implicated in the activation of NK cells. In RCC, VHL mutations induce constitutive activation and accumulation of Hypoxia-inducible factor (HIF). Certain VHL mutations correlate with low HLA-I molecules expression via a partially HIF-dependent pathway. The low expression of HLA-I molecules by VHL-mutated RCC cells reduces the engagement of NKG2A inhibitory receptor, shifting the balance toward NK cell activation. Membrane HLA-G molecules upregulate inhibitory receptors (NKG2A,and ILT2) on NK cells. Membrane-bound IL15 (Mb-IL15) is involved in NK cell activation and survival. In CML, the oncogeneic protein bcr/abl induces the expression of ICAM-1 and NKG2D ligands on myeloid cells favoring NK/target conjugates and lysis. Altered IFNγ signaling in bcr/abl target maintains a low HLA-I molecules expression. Bcr/abl dendritic cells activate NK cells via NKG2D receptor. Imatinib mesylate interferes with NK/leukemic targets. DC: Dendritic cell; IM: Imatinib Mesylate; IRF: Interferon regulatory factor; STAT-1: Signal Transducer and Activator of Transcription factor-1.

Figure 3. Proposed hypotheses to explain the alterations of NK cells in cancers patients. NK cells are present in different body compartments (peripheral, blood, secondary lymphoid organs and tissues) and NK defects may depend on where NK and tumor cells encounter: (1) Circulating tumor cells (CTC) may directly affect the phenotype and function of blood NK cells; (2) metastatic cells invading certain sites of NK cell maturation (i.e., LN) can influence final differentiation of NK cell subsets; (3) Compared with NK cells in normal tissue, NK-TILs are dysfunctional. Cancer cells can directly affect the functional status of tissue resident NK cells or of recruited NK-TILs by cell-to-cell contacts or by the secretion of soluble immunosuppressive factors; (4) NK-TILs may return to blood contributing to the altered phenotype observed on circulating NK cells. Finally, cytotoxic drugs and targeted therapies can interfere with NK cell activation, affecting (directly or indirectly) their phenotype or signaling pathways.