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 cytokineproducing 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.

The Role of Activating and Inhibitory NK Cell Receptors in Antitumor Immune Response

“…These data indicate that activating NKG2D receptor has a role in NK cell tumor immunosurveillance and in immune-mediated rejection of tumor cells and that NKG2D downregulation as a consequence of tumor immunoediting favors tumor progression [13].…”

“…Similarly, as NKp30 is comprised of three diferent isoforms, NKp30a, b, and c it has been shown that binding of NKp30c induces an immunosuppressive signal by producing IL-10 that is associated with reduced NK cell efector functions. Therefore, the inal outcome of NKp44 and NKp30 activation depends on the presence of ligands on target cells, as well as receptor isoforms expressed on the surface of NK cells, respectively [13].…”

“…1). These factors generate a chronic inlammatory immunosuppressive milieu that leads to the suppression of the antitumor efector NK cell function that supports tumor progression [3,7,13,65]. In this sense, considering that the expression of activating NK cell receptors is decreased in most malignancies, and as some studies report that the expression of inhibitory KIR and CD94/ NKG2A receptors on NK cells in diferent tumors remains unchanged, this suggests that activating receptors are main targets of tumor-mediated suppression [13].…”

STAT5 Loss Awakens the Dark Force in Natural Killer Cells

“…Individuals with high NK cell activity have a lower risk to develop cancer ( 2 ). NK cell infi ltration in the tumor is frequently correlated with improved prognosis for patients with cancer, and in many mouse tumor models depletion of NK cells leads to accelerated tumor growth ( 1 ). These studies imply an important role of NK cells in tumor immunosurveillance and support clinical application of NK cell-based therapies in the clinic for cancer treatment.…”

“…Within the tumor microenvironment the interaction of tumor cells and immune cells critically shapes the progression of malignant disease ( 1 ). There is now increasing evidence that certain types of immune cells have the potential not only to effi ciently control, but also to promote tumor growth.…”