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ALPN‐101 (ICOSL vIgD‐Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first‐in‐human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN‐101 in healthy adult subjects. ALPN‐101 was generally well‐tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN‐101 exhibited a dose‐dependent increase in exposure with an estimated terminal half‐life of 4.3–8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN‐101 resulted in a dose‐dependent increase in maximum target saturation and duration of high‐level target saturation. Consistent with its mechanism of action, ALPN‐101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T‐dependent B cell responses, respectively. In conclusion, ALPN‐101 was well‐tolerated in healthy subjects with dose‐dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN‐101 in inflammatory and/or autoimmune diseases is therefore warranted.

In a 24-week trial involving patients with rheumatoid arthritis that was refractory to biologic agents, the JAK1 inhibitor upadacitinib was superior to the T-cell costimulation modulator abatacept in reducing disease activity as assessed by a composite measure of joint changes and C-reactive protein level.

Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, although the appropriate targets for intratumoral immunomodulation using this strategy are not known. Here we find that intratumoral therapy with Newcastle disease virus (NDV), in addition to the activation of innate immunity, upregulates the expression of T-cell co-stimulatory receptors, with the inducible co-stimulator (ICOS) being most notable. To explore ICOS as a direct target in the tumour, we engineered a recombinant NDV-expressing ICOS ligand (NDV-ICOSL). In the bilateral flank tumour models, intratumoral administration of NDV-ICOSL results in enhanced infiltration with activated T cells in both virus-injected and distant tumours, and leads to effective rejection of both tumours when used in combination with systemic CTLA-4 blockade. These findings highlight that intratumoral immunomodulation with an oncolytic virus expressing a rationally selected ligand can be an effective strategy to drive systemic efficacy of immune checkpoint blockade. Oncolytic viruses induce a variety of immune targets in the infected tumours. Here, the authors show that Newcastle Disease Virus (NDV) upregulates the inducible co-stimulator (ICOS) on T cells and that intratumoral targeting of ICOS with engineered NDV in combination with CTLA-4 blockade induces systemic anti-tumour immunity in mice.

Follicular regulatory T cells control humoral immune responses, but how these cells are in turn controlled has been unclear. Sharpe and colleagues demonstrate that signaling via PD-1 regulates number and function of these cells. CD4 + CXCR5 + Foxp3 + follicular regulatory T cells (T FR cells) inhibit humoral immunity mediated by CD4 + CXCR5 + Foxp3 − follicular helper T cells (T FH cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of T FR cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of T FR cells in the lymph nodes and that those T FR cells had enhanced suppressive ability. We also found substantial populations of T FR cells in mouse blood and demonstrated that T FR cells in the blood homed to lymph nodes and potently inhibited T FH cells in vivo . T FR cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

Group 2 innate lymphoid cells (ILC2s) play a crucial role in inducing type 2 inflammation in the lungs in response to allergens. Our study investigated the regulatory mechanism of IL-10 production by ILC2s and its impact on airway hyperreactivity (AHR), focusing on the role of ICOS. We found that inhibiting ICOS in pulmonary ILC2s significantly enhanced IL-10 production. The absence of ICOS reprogrammed ILC2 steroid metabolism, leading to increased cholesterol and cortisol biosynthesis and subsequent glucocorticoid receptor (GR) activation. This reprogramming regulated MAF and NFIL3 activation, promoting IL-10 production. Notably, in vivo GR inhibition or ILC2-specific GR deficiency exacerbated AHR development in multiple mouse models. We extended these findings to human ILC2s, demonstrating concordant results between murine models and human cells. Our results indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. This mechanism provides new insights into the complex interplay between ILC2s, ICOS, and glucocorticoid signaling in the context of allergic airway inflammation.

Memory B cells (B mem cells) are the basis of long-lasting humoral immunity. They respond to re-encountered antigens by rapidly producing specific antibodies and forming germinal centers (GCs), a recall response that has been known for decades but remains poorly understood. We found that the receptor for the cytokine IL-9 (IL-9R) was induced selectively on B mem cells after primary immunization and that IL-9R-deficient mice exhibited a normal primary antibody response but impaired recall antibody responses, with attenuated population expansion and plasma-cell differentiation of B mem cells. In contrast, there was augmented GC formation, possibly due to defective downregulation of the ligand for the co-stimulatory receptor ICOS on B mem cells. A fraction of B mem cells produced IL-9. These findings indicate that IL-9R signaling in B mem cells regulates humoral recall responses. Signaling via the cytokine IL-9 receptor regulates humoral recall responses. Kitamura and colleagues report that IL-9 triggers memory B cells to proliferate and terminally differentiate into antibody-secreting cells rather than re-entering germinal centers.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation. Roquin-1 is a posttranscriptional regulator that controls the expression of many immune-related genes such as ICOS and TNFA . Here, the authors report a homozygous R688* loss of function mutation in Roquin-1 in a patient with syndromic uncontrolled hyperinflammation associated with immune cell activation and hypercytokinemia.

Background ICOS (inducible T‐cell co‐stimulator) and ICOS ligand (ICOSL) are part of an important, complex pathway that can lead to both immune stimulation and suppression. ICOS and ICOSL have heterogeneous expression patterns between and within tumor types. Methods This review provides an overview of ICOS and ICOSL, their mechanisms of action, expression in cancer and other diseases, and clinical trials exploring therapies targeting ICOS. Results Because of the bidirectional immune impact of the ICOS/ICOSL signaling pathway, both ICOS agonists and antagonists are under development and evaluation in clinical trials. The majority of clinical trials have focused on the development of ICOS agonists, with only one study exploring an ICOS antagonist; there have been no clinical trials developing ICOSL agonists or antagonists in oncology. ICOS can be expressed on immune‐activating effector T‐cell and immunosuppressive regulatory T‐cell (Tregs). Thus, it is critical to determine where and how ICOS is expressed in order to evaluate the role for agonists versus antagonists. To date, ICOS agonists have shown limited activity in patients with malignancies, perhaps because of the lack of biomarker‐based trials. However, an ICOS antagonist demonstrated a 44% response rate in angioimmunoblastic T‐cell lymphoma; ICOS is highly expressed on T‐follicular helper cells (type of CD4 cell) and proliferation of these cells may be a pathogenic mechanism for these lymphomas. A role for the ICOS/ICOSL signaling pathway has also been implicated outside of oncology, including in viral infections such as COVID‐19, and in autoimmune conditions such as asthma and systemic lupus erythematosus. Conclusion Biomarker‐driven approaches will be important to individualize therapy and ascertain which cancer patients will derive the greatest benefit from ICOS‐directed combination therapy approaches. ICOS (inducible T‐cell co‐stimulator) and ICOS ligand (ICOSL) are part of an important, complex pathway that can lead to both immune stimulation and suppression. Both ICOS agonists and antagonists are under development as oncology therapeutics and biomarker driven approaches will be important to ascertain which patients will derive the greatest benefit these therapies.

Signaling via the inducible costimulator ICOS drives the stepwise development of follicular helper T cells. Kong and colleagues describe an ICOS–kinase TBK1 signaling pathway that specifies the commitment of these cells. Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (T FH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) T FH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of T FH cells. These results reveal a previously unknown ICOS-TBK1 signaling pathway that specifies the commitment of GC T FH cells.

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4(+) T cells and induced regulatory CD4(+) T cells (CD4(+) iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4(hi) Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4(hi) Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4(hi) Treg induced by allogeneic CD40-activated B cells. More importantly, CD4(hi) Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4(hi) Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4(hi) Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4(hi) Treg and uncover a novel relationship between ICOS and CTLA-4.