NK Cell-Based Immunotherapy in Renal Cell Carcinoma

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients’ survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities.

Arrested development: suppression of NK cell function in the tumor microenvironment

“…Their endogenous anti‐tumor role in vivo has been demonstrated in mouse models of NK cell deficiency that develop more carcinogen‐induced tumors, oncogene‐driven tumors, and experimental lung and liver metastases 2–4 . Similarly, collective clinical evidence suggests that increased presence of NK cells correlates with better survival outcomes in multiple solid cancers and in response to checkpoint blockade immunotherapy in melanoma 5–9 . In mice, NK cells have been shown to be one of the earliest circulating lymphocytes recruited to distal sites of tumor metastasis and can mediate cancer regression through IFN‐γ production, rapid cytotoxicity, and recruitment and proliferation of type 1 conventional dendritic cells (cDC1) through production of XCL1 and FLT3 ligand 10,11 .…”

“…[2][3][4] Similarly, collective clinical evidence suggests that increased presence of NK cells correlates with better survival outcomes in multiple solid cancers and in response to checkpoint blockade immunotherapy in melanoma. [5][6][7][8][9] In mice, NK cells have been shown to be one of the earliest circulating lymphocytes recruited to distal sites of tumor metastasis and can mediate cancer regression through IFN-c production, rapid cytotoxicity, and recruitment and proliferation of type 1 conventional dendritic cells (cDC1) through production of XCL1 and FLT3 ligand. 10,11 NK cell activation is regulated by a balance of activating and inhibitory receptors such as natural cytotoxicity receptors (NCRs) 12,13 or killer cell lectin-like receptor (NKG2) molecules NKG2D 14 and NKG2A, respectively 15 ; killer cell immunoglobulin-like receptors (KIRs) in humans, and the mouse counterpart c-type lectin-like (Ly49) receptors.…”

Remodeling of Stromal Cells and Immune Landscape in Microenvironment During Tumor Progression

“…Targeting this receptor would help in the activation of other NK cell receptors that lead to cytokine release and the killing of tumor cells. Gauthier and co-workers developed a multifunctional antibody (NKp46 specific) targeting CD19, CD20, or EGFR as tumor antigens and triggering tumor killing by NK cells ( 151 , 152 ). CD73 is another immune checkpoint that defines regulatory NK cells within TME.…”

Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

“…They can also release a wide variety of cytokines and chemokines that promote an adaptive immune response against target cells. Thus, NK cells represent a valuable tool in cancer immunotherapy, and several strategies have been proposed to exploit and improve their anti-tumor mechanisms in different cancers [1][2][3][4] . Among them, a promising therapeutic approach is to stimulate NK cells with interleukins (ILs).…”