Abstract
Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherapies for solid tumors.
Highlights
As a central part of the innate lymphoid cells (ILCs), Natural killer (NK) cells are cytotoxic large granular lymphocytes capable of killing tumor cells and viral-infected cells without the prerequisite of priming [1]
TGF-β is largely produced by tumor cells, regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment (TME), and it has a strong association with poor prognosis in lung carcinoma [77], pancreatic cancer [78], gastric cancer [79], colorectal cancer [80], and hepatocellular carcinoma [81]
Treatment with anti-CD96 monoclonal antibody (mAb) can inhibit the progression and metastasis of melanoma, lung carcinoma and prostate carcinoma through promoting NK cell anti-cancer activity in an IFN-γ-dependent manner. When it is used in combination with anti-programmed cell death 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb, there is a further increase in NK cell infiltration and IFN-γ production in metastatic melanoma model [155]
Summary
As a central part of the innate lymphoid cells (ILCs), NK cells are cytotoxic large granular lymphocytes capable of killing tumor cells and viral-infected cells without the prerequisite of priming [1]. Despite the great success of NK adoptive immunotherapy achieved in hematologic cancers, the microenvironment of solid cancers severely blunts NK-mediated cytotoxicity by reducing infiltration, impairing target cells recognition, suppressing activation, as well as weakening immunoregulatory and cytotoxic functions of NK cells [11,12]. Restoring NK-mediated immunosurveillance would provide a promising therapeutic target for patients suffering from solid tumors. NK cells-targeting immunotherapies, including the traditional cytokine administration, ICIs, bi-specific or tri-specific killer cell engagers (BiKEs or TriKEs), and the more recently developed genetically modified NK cells such as CAR-NKs, have been exploited and optimized to restore NK immunity in the immunosuppressive microenvironment [13,14]. We analyze the challenges and therapeutic strategies for NK recruitment, recognition, activation and function in solid tumors, while evaluating the advantages and disadvantages of different categories of immunotherapies
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