Natural killer (NK) cells are innate immune effectors capable of broad cytotoxicity via germline-encoded receptors and can have conferred cytotoxic potential via the addition of chimeric antigen receptors. Combined with their reduced risk of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), NK cells are an attractive therapeutic platform. While significant progress has been made in treating hematological malignancies, challenges remain in using NK cell-based therapy to combat solid tumors due to their immunosuppressive tumor microenvironments (TMEs). The development of novel strategies enabling NK cells to resist the deleterious effects of the TME is critical to their therapeutic success against solid tumors. In this review, we discuss strategies that apply various genetic and non-genetic engineering approaches to enhance receptor-mediated NK cell cytotoxicity, improve NK cell resistance to TME effects, and enhance persistence in the TME. The successful design and application of these strategies will ultimately lead to more efficacious NK cell therapies to treat patients with solid tumors. This review outlines the mechanisms by which TME components suppress the anti-tumor activity of endogenous and adoptively transferred NK cells while also describing various approaches whose implementation in NK cells may lead to a more robust therapeutic platform against solid tumors.
Background Natural killer cells (NKs) expressing chimeric antigen receptors (CAR-NKs) were successful in hematological malignancies. 1 However, solid tumors resist CAR-NKs via a tumor microenvironment (TME) that includes myeloid derived suppressor cells (MDSCs) and M2 macrophages (M2s). 2 We demonstrated that ex vivo manufacture of therapeutic CAR-NKs significantly upregulated T cell immunoreceptor with Ig and ITIM domains (TIGIT), an inhibitory NK receptor. Analysis of pediatric neuroblastoma and sarcoma patient tumors confirmed high expression of TIGIT ligands on tumor cells and intra-tumoral MDSCs and M2s. Our main objective was to determine influence of TIGIT on CAR-NK function in the TME. Current TIGIT-targeting approaches using antibodies are handicapped by poor bioavailability and transient binding in the TME. We hypothesized that genetic deletion of TIGIT on CAR-NKs will lead to a more profound and durable antitumor response within the TME. 3 Methods TIGIT knockout (KO) CAR-NKs expressing a GD2.4-1BB.zeta CAR were generated by concurrent CRISPR/ cas9 and retroviral transduction of expanded primary human NK cells. Degranulation (CD107a) and IFN-g by TIGIT KO . GD2.
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