Abstract
Immunotherapy has transformed cancer treatment by promoting durable clinical responses in a proportion of patients; however, treatment still fails in many patients. Innate immune cells play a key role in the response to immunotherapy. Crosstalk between innate and adaptive immune systems drives T-cell activation but also limits immunotherapy response, as myeloid cells are commonly associated with resistance. Hence, innate cells have both negative and positive effects within the tumor microenvironment (TME), and despite investment in early clinical trials targeting innate cells, they have seen limited success. Suppressive myeloid cells facilitate metastasis and immunotherapy resistance through TME remodeling and inhibition of adaptive immune cells. Natural killer (NK) cells, in contrast, secrete inflammatory cytokines and directly kill transformed cells, playing a key immunosurveillance role in early tumor development. Myeloid and NK cells show reciprocal crosstalk, influencing myeloid cell functional status or antigen presentation and NK effector function, respectively. Crosstalk between myeloid cells and the NK immune network in the TME is especially important in the context of therapeutic intervention. Here we discuss how myeloid and NK cell interactions shape anti-tumor responses by influencing an immunosuppressive TME and how this may influence outcomes of treatment strategies involving drugs that target myeloid and NK cells.
Highlights
Immunotherapy has transformed cancer treatment by harnessing the immune system to target solid and hematological cancers [1], achieving durable responses across multiple tumor types [2]
Most solid tumors include a variety of immunosuppressive cells, such as regulatory T cells, polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSCs), mononuclear MDSCs (M-MDSCs), tumor-associated macrophages (TAMs) [as defined by Bronte et al, [6]] and neutrophils that can suppress effector CD8+ T cells and Natural killer (NK) cells [7]
Pathogen-induced upregulation of ligands for activating NK-cell receptors can result in the elimination of monocytes and macrophages by NK cells [25], as well as the killing of immature but not mature dendritic cells in vitro [26], a process thought to limit the generation of potentially tolerogenic dendritic cells
Summary
Immunotherapy has transformed cancer treatment by harnessing the immune system to target solid and hematological cancers [1], achieving durable responses across multiple tumor types [2]. The most advanced therapies are those that modulate myeloid cells, depleting or inhibiting recruitment or promoting reprogramming to activate or de-repress tumoricidal mechanisms [9], but these modalities have been disappointing in the clinic (Table 1). These trials include inhibitors of CSF1R, CCR2, CXCR2, CXCR4, and most recently, PI3Kg [10, 11]. N contrast, only a few drugs targeting NK biology to reverse NK tumor immune tolerance have been progressed to clinical trials (Table 1) These therapies include the anti–KIR2DL-1, -2, and -3 antibody IPH2102/BMS-986015 (lirilumab), the antiNKG2A antibody IPH2201 (monalizumab), and the anti-CD16 innate cell engager AFM13.
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