Avoiding immune destruction is a hallmark of cancer. Natural killer (NK) cells contribute to tumor immune surveillance and protection from tumor metastasis. The cell surface Ig superfamily molecule CD96 has recently been shown as a negative regulator of mouse NK cell activity, and we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in multiple tumor models. The anti-metastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1) and IFN-γ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti-CTLA4, anti-PD1, anti-TIGIT, or doxorubicin chemotherapy. Development of additional anti-mouse and anti-human CD96 mAbs will be discussed. Overall these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases. The activity of NK cells is also governed by the cytokine IL-15, foreign and self-ligands, and a variety of immunosuppressive factors. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical negative regulator of IL-15 signalling in NK cells and shown the critical intrinsic role of CIS in suppressing NK cell control of tumor initiation and metastasis. The combination of Cish-deficiency and relevant immunotherapies, such as immune checkpoint blockade antibodies, IL-2, and type I interferon revealed further improved control of metastasis. The data clearly indicates that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. The relative importance of mechanisms that tumors adopt to evade NK cells remains ill defined. Using mice with NK cells that either constitutively, or are unable to, signal via the TGF-β receptor, revealed that TGF-β signaling induces the transdifferentiation of conventional NK (cNK) cells into ILC1. Functional analysis revealed that host protection from tumor initiation and metastasis is mediated by cNK cells, whereas tumor resident ILC1 and ILC1-like cells appear to offer no host protection. These data indicate the plasticity of cNK cells under pathophysiological conditions and a potential new escape mechanism for tumors from innate immunity.

Citation Format: Mark J. Smyth, Eva Putz, Stephen Blake, Aaron Gao, Fernando Guimaraes, John Miles, Bill Dougall, Michele WL Teng, Nicholas D. Huntington. Novel natural killer cell targets for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA27.