Immune checkpoints orchestrate a complex regulatory network, tasked with keeping the immune system in check to avoid autoimmune and inflammatory disease. The field is dominated by development of new checkpoint blockers to treat cancer and infectious diseases, following the success of antibody therapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) that have revolutionized cancer treatment. Regulatory T cells (Tregs) and members of a family of intracellular regulators called suppressors of cytokine signaling (CIS, SOCS1, SOCS2 and SOCS3) are also central to limiting the immune response. SOCS1 is a key checkpoint in the immune response to cancer and infection, SOCS3 in various inflammatory diseases, and together they allow crosstalk between cytokines in non-immune and immune cells. CIS (CISH gene) is a critical checkpoint in natural killer (NK) and T cell control of cancer, while SOCS2 has been reported to have roles in controlling allergy and cancer, including acute myeloid leukemia. Many of these regulatory players are interconnected and interdependent. In fact, SOCS1 was shown to stabilize Foxp3+ Treg peripheral cells. There is also evidence that SOCS1 can regulate other checkpoint players such as PD-1, via inhibition of interferon signaling. Thus, manipulation of SOCS activity or levels could influence other checkpoint factors.

Given that the SOCS proteins are intracellular checkpoint regulators, the challenge is to positively and negatively regulate these molecules in an informative way with potential for therapeutic translation. In this regard, a peptide mimetic of the key SOCS1 kinase inhibitory region (KIR) referred to as “SOCS1-KIR,” binds to the catalytic site of Janus kinases JAK2 and TYK2 and thus blocks both type II and type I interferon (IFN) signaling. In addition, SOCS1-KIR can bind to the MyD88 associated adaptor protein (MAL) and regulate signaling emanating through toll like receptors 2 and 4 (TLR2 and 4). When palmitated or polycationated by polyarginines, or encapsulated in hydrogels, SOCS1-KIR can penetrate the cell membrane and is an effective therapy in models of multiple sclerosis and lupus. By contrast, a peptide corresponding to the JAK2 activation loop blocks SOCS1/3 activity and enhances the immune response against a broad range of viral infections, including SARS-CoV-2; and has potent anti-melanoma activity in an aggressive mouse melanoma model. SOCS3 is associated with several metabolic disorders, most significantly the inhibition of insulin and leptin signaling in obesity and type 2 diabetes.

Despite several fundamental publications, there appears to be a lack of awareness that the SOCS are key immune checkpoints. This was reflected in a recent call for innovative immune checkpoint inhibitors, which neglected to mention the SOCS system. This may be because unlike PD-1 and CTLA-4 which can be targeted by antibodies, regulation of SOCS activity presents a unique challenge due to their intracellular location, and the inherent difficulty of targeting the conserved SH2 or SOCS box function. Contrary to this perception, there are multiple strategies, including gene editing, anti-sense oligonucleotides, microRNAs and intracellular antibodies, that could be used to manipulate SOCS function. The recent development of a chemical SOCS2-SH2 inhibitor also offers hope that this domain is not as intractable as previously thought. Notably, effective peptidomimetic agonists and antagonists, as indicated above, have been developed with potential for treatment of viral and bacterial infections, cancer, autoimmune and inflammatory diseases, as well as the cellular dysregulation associated with type 2 diabetes. This Research Topic aims to explore these various SOCS related disorders and present an approach to their amelioration. We believe the controlled modulation of certain SOCS proteins to dampen or enhance immune and non-immune functions will provide a needed innovation in the immune checkpoint field.

We are interested in Original Research, Review, and Perspective articles, focusing on but not limited to the following areas:
1. SOCS as checkpoint modulators. This is not obvious based on the current literature.
2. SOCS mimetics and antagonists as regulators of intracellular checkpoint activity. The intracellular nature of SOCS and the difficulty in assessing in the context of therapeutics probably plays a role in “ignoring” SOCS in checkpoint inhibitions.
3. SOCS role in autoimmune and inflammatory disorders. There are ample examples of SOCS playing a role in lupus, multiple sclerosis, inflammatory eye disorders, arthritis, etc.
4. Role of SOCS3 in insulin resistance and type 2 diabetes. SOCS3 plays a role in a major health issue but is little recognized for this.
5. Role of SOCS proteins in viral infections in general. There is a plethora of examples here with a variety of viruses including SARS-CoV-2.
6. Role of SOCS proteins in bacterial infections. There is evidence that SOCS may play a role in methicillin-resistant Staphylococcus aureus (MRSA) infections.
7. Role of SOCS in COVID-19 pandemic. This viral pandemic represents a special case in terms of a demonstrated SOCS connection.
8. Role of SOCS in cancer immunotherapy. PD-1 is highly cited as a checkpoint target but seems effective only in limited situations.
9. Crosstalk between SOCS and regulatory T cells (Tregs). Tregs are too important to ignore their checkpoint modulator interactions, including those involving SOCS.
10. SOCS modulation of the immune system with possible focus on specific areas such as natural killer (NK) cell activity. NK cell function has been extensively shown to be regulated by SOCS.

Professor Sandra Nicholson and Dr. Karen Doggett are employees of the Walter and Eliza Hall Institute, which receives milestone and royalty payments related to venetoclax; Professor Nicholson receives a share of these royalties from the Institute. The Walter and Eliza Hall Institute also receives milestone payments from ONK Therapeutics Ltd and Servier, an international pharmaceutical governed by non-profit, FIRS; Professor Nicholson receives benefits related to these payments. Professor Sandra Nicholson and Dr. Karen Doggett have received research funding from Servier. The other topic editors declare no competing interests with regard to the topic theme.

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