Combination Immune Therapies to Enhance Anti-Tumor Responses by NK Cells

Abstract

Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma.

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

“…Indeed, DLBCL cells can constitutively express NKG2D ligands, that may be further enhanced by chemotherapy-triggered DNA damage response. [29][30][31][32][33][34]56,57 Overall, our results suggest that the therapy-driven, CD16-dependent, continuous stimulation leads to a prolonged NK cell phenotypic modulation and in vitro functional impairment. These alterations may be highly significant also for in vivo NK cell cytotoxic activity against DLBCL cells, and as such, may impact rituximab-based therapy efficacy.…”

NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

“…Therapies to potentiate NK cell function in CLL patients could include lenalidomide, bortezomib, and cytokines. [59][60][61][62] Patients and methods…”

Imaging of Cell–Cell Communication in a Vertical Orientation Reveals High-Resolution Structure of Immunological Synapse and Novel PD-1 Dynamics

“…Programmed cell death protein 1 (PD-1) is an emerging immune checkpoint protein highly up-regulated in T, B, and NK cells in the setting of chronic viral infection and tumorigenesis (54, 55). Similar to other inhibitory receptors such as KIR and CD94/NKG2A, the intracellular domain of PD-1 contains an immunoreceptor tyrosine inhibitory motif (ITIM), which plays a critical role in NK cell inhibition (56).…”