The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention.

Ag-specific tolerizing immunotherapy is considered the optimal strategy to control type 1 diabetes, a childhood disease involving autoimmunity toward multiple islet antigenic peptides. To understand whether tolerizing immunotherapy with a single peptide could control diabetes driven by multiple Ags, we coencapsulated the high-affinity CD4+ mimotope (BDC2.5mim) of islet autoantigen chromogranin A (ChgA) with or without calcitriol (1α,25-dihydroxyvitamin D3) into liposomes. After liposome administration, we followed the endogenous ChgA-specific immune response with specific tetramers. Liposome administration s.c., but not i.v., induced ChgA-specific Foxp3+ and Foxp3− PD1+ CD73+ ICOS+ IL-10+ peripheral regulatory T cells in prediabetic mice, and liposome administration at the onset of hyperglycemia significantly delayed diabetes progression. After BDC2.5mim/calcitriol liposome administration, adoptive transfer of CD4+ T cells suppressed the development of diabetes in NOD severe combined immunodeficiency mice receiving diabetogenic splenocytes. After BDC2.5mim/calcitriol liposome treatment and expansion of ChgA-specific peripheral regulatory T cells. IFN-γ production and expansion of islet-specific glucose-6-phosphatase catalytic subunit–related protein–specific CD8+ T cells were also suppressed in pancreatic draining lymph node, demonstrating bystander tolerance at the site of Ag presentation. Thus, liposomes encapsulating the single CD4+ peptide, BDC2.5mim, and calcitriol induce ChgA-specific CD4+ T cells that regulate CD4+ and CD8+ self-antigen specificities and autoimmune diabetes in NOD mice.

Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host’s immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host–pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8⁺ and CD4⁺ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.

Prevention or reversal of T cell exhaustion is a major objective of cancer immunotherapy. However, few models exist to generate, characterize and modulate exhausted human T cells, particularly within solid tumors in vivo, which likely hampers the discovery and translation of novel therapeutics. In this study we describe a humanized mouse model where functional human CD8+ T cells specific for the tumor antigen NY-ESO-1 develop in vivo from human CD34+ hematopoietic stem cells genetically modified to express a HLA-A *0201-restricted NY-ESO-1 specific T cell receptor (TCR). HLA-A *0201+ NY-ESO-1+ expressing A375 melanoma tumors engrafted in these mice and were refractory to treatment with anti-PD-1 despite being infiltrated with NY-ESO-1 specific T cells. Tumor-Infiltrating Lymphocytes (TIL) upregulated tissue resident memory (TRM) markers CD103 and CD69 along with exhaustion markers PD-1, TIGIT, and CD39 relative to T cells from other organs. Further, TILs failed to secrete cytokines TNF and IFNγ following in vitro stimulation with conventional Type I Dendritic Cells (cDC1), indicative of terminal exhaustion. However, cDC1 stimulation of the terminally exhausted NY-ESO-1 specific TILs led to enhanced tumor killing that was associated with increased CD107a and Granzyme B expression that was restricted to a subset of CD226+ NY-ESO-1 specific TILs. These findings establish a novel platform to investigate T cell exhaustion in human tumors and suggest a role for cDC1 in enhancing terminally exhausted TIL cytotoxic function.