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Over recent years, the use of immune checkpoint inhibitors (ICI) has progressed to first and second-line treatments in several cancer types, transforming patient outcomes. While these treatments target T cell checkpoints, such as PD-1, LAG3 and CTLA-4, their efficacy can be compromised through adaptive resistance whereby tumors acquire mutations in genes regulating neoantigen presentation by MHC-I [93]. ICI-responsive tumor types such as advanced metastatic melanoma typically have a high mutational burden and immune infiltration; however, most patients still do not benefit from ICI monotherapy for a number of reasons [94]. This highlights the need for novel immunotherapy strategies that evoke the immune control of tumor cells with low neoantigen/MHC-I expression, overcome immune suppressive tumor microenvironments and promote tumor inflammation. In this regard, targeting natural killer (NK) cells may offer a solution to some of these bottlenecks.

Section snippetsIL-15 signalling as an intracellular checkpoint in NK cells

The NK cell activity is not governed by a dominant antigen receptor, thus, the ligation of classic immune checkpoints such as PD1 and LAG3 are not thought to inhibit NK cell function in the same manner as CD8 + T cells 32, 75. Indeed, in several murine tumor models and human tumors, PD1 expression is infrequent in NK cells and PD1 is not upregulated in NK cells following activation in vitro [33]. Unlike CD8 + T cells, which rely on this dominant antigen receptor (TCR) interaction with MHC-I for

Summary

Following the clinical success of inhibiting the T-cell immune checkpoints PD-1, LAG3 and CTLA-4, it is enticing to identify orthogonal immune checkpoints, which can be targeted to further augment anti-tumor immune responses. The family of SOCS proteins are potent negative regulators of an array of essential immune signalling processes, most notably the JAK/STAT pathway. Targeting SOCS proteins such as CIS and SOCS1 in preclinical models results in enhanced cytotoxic immune cell function and

Declaration of Competing Interest

N.D.H. is a founder and shareholder in oNKo-Innate. N.D.H serves on an advisory board for Bristol Myers Squibb. N.D.H. is an inventor of patents relating to this work. All other authors declare no competing interests.

Acknowledgements

Our laboratory is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (GNT1124784, GNT1066770, GNT1057852, GNT1124907, GNT1057812, GNT1049407, GNT1027472, and GNT1184615) and an NHMRC Investigator Fellowship (GNT1195296) to N.D.H. N.D.H. is a recipient of a Melanoma Research Grant from the Harry J. Lloyd Charitable Trust, Melanoma Research Alliance Young Investigator Award, Cancer Council of Victoria Grant-in-aid, the National Foundation for

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