The Impact of NK Cell-Based Therapeutics for the Treatment of Lung Cancer for Biologics: Targets and Therapy

Abstract

Lung cancer has a dismal prognosis and novel targeted therapies leave still room for major improvements and better outcomes. Immunotherapy targeting immune checkpoint (IC) proteins, either as single agents or in combination with chemotherapy, is active but responders constitute only approximately 10-15% of non-small cell lung cancer (NSCLC) patients. Other effector immune cells such as CAR-T cells or NK cells may help to overcome the limitations of the IC inhibitor therapies for lung cancer. NK cells can kill tumor cells without previous priming and are present in the circulatory system and lymphoid organs. Tissue-residing NK cells differ from peripheral effector cells and, in case of the lung, comprise CD56bright CD16-negative populations showing high cytokine release but low cytotoxicity in contrast to the circulating CD56dim CD16-positive NK cells exhibiting high cytotoxic efficacy. This local attenuation of NK cell killing potency seems due to a specific stage of NK differentiation, immunosuppressive factors as well as presence of myeloidderived suppressor cells (MDSCs) and regulatory T cells (TREGs). Improved NK cell-based immunotherapies involve IL-2-stimulated effector cells, NK cells expanded with the help of cytokines, permanent NK cell lines, induced pluripotent stem cell-derived NK cells and NK cells armed with chimeric antigen receptors. Compared to CAR T cell therapy, NK cells administration is devoid of graft-versus-host disease (GvHD) and cytokine-release syndrome. Although NK cells are clearly active against lung cancer cells, the low-cytotoxicity differentiation state in lung tumors, the presence of immunosuppressive leucocyte populations, limited infiltration and adverse conditions of the microenvironment need to be overcome. This goal may be achieved in the future using large numbers of activated and armed NK cells as provided by novel methods in NK cell isolation, expansion and stimulation of cytotoxic activity, including combinations with monoclonal antibodies in antibody-dependent cytotoxicity (ADCC). This review discusses the basic characteristics of NK cells and the potential of NK cell preparations in cancer therapy.

Harnessing Natural Killer Cells in Non-Small Cell Lung Cancer

“…The majority of the NK cell population in the lung is CD56 bright CD16 - , exhibiting high cytokine release but low cytotoxicity [ 48 ]. In fact, in vivo studies have demonstrated that human lung NK cells respond poorly to activation by target cells, when compared to peripheral blood NK cells.…”

“…In fact, in vivo studies have demonstrated that human lung NK cells respond poorly to activation by target cells, when compared to peripheral blood NK cells. It has been proposed that this is due to the suppressive effects associated with alveolar macrophages and soluble factors that are present in the epithelial lining of the lower respiratory tract to maintain lung homeostasis [ 48 , 49 ]. These human lung NK cells share several phenotypic similarities with the decidual NK (dNK) cells present in the maternal decidua during pregnancy [ 50 ].…”

The Advantages and Challenges of Anticancer Dendritic Cell Vaccines and NK Cells in Adoptive Cell Immunotherapy

“…Purified NK cells had demonstrated evidence of therapeutic potential for a wide variety of human malignancies, including sarcomas [52], myeloma [53], carcinomas [54][55][56], lymphomas [57], and leukemia [1,58]. However, the clinical efficacy and application of NK cell immunotherapy have been limited by the inability to obtain sufficient cell numbers for adoptive transfer, as these cells represent a small fraction of peripheral white blood cells, expand poorly ex vivo, and have limited life spans in vivo.…”

A validated nomogram integrating baseline peripheral T-lymphocyte subsets and NK cells for predicting survival in stage I–IIIA non-small cell lung cancer after resection

“…Functionally, NK cells can produce cytokines that support T helper polarization and T cell activation, as well as stimulate dendritic cell (DC) and B cell maturation to bridge and orchestrate innate and adaptive immune responses (27). Hence, NK cells play an important role in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against malignancies, and dependent on successful further rearming and mobilization, against solid tumors in the future (28). However, there are currently few studies on the relationship between the prognosis of stage I-IIIA NSCLC after resection and peripheral T-lymphocyte subsets combined with CD16+56 NK cells.…”