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Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).

Cancer stem cells (CSCs), also known as tumor-initiating cells, are characterized by an increased capacity for self-renewal, multipotency, and tumor initiation. While CSCs represent only a small proportion of the tumor mass, they significantly account for metastatic dissemination and tumor recurrence, thus making them attractive targets for therapy. Due to their ability to sustain in dormancy, chemo- and radiotherapy often fail to eliminate cancer cells with stemness properties. Recent advances in the understanding of the tumor microenvironment (TME) illustrated the importance of the immune contexture, determining the response to therapy and clinical outcome of patients. In this context, CSCs exhibit special properties to escape the recognition by innate and adaptive immunity and shape the TME into an immunosuppressive, pro-tumorigenic landscape. As CSCs sculpt the immune contexture, the phenotype and functional properties of the tumor-infiltrating immune cells in turn influence the differentiation and phenotype of tumor cells. In this review, we summarize recent studies investigating main immunomodulatory properties of CSCs and their underlying molecular mechanisms as well as the impact of immune cells on cancer cells with stemness properties. A deeper understanding of this bidirectional crosstalk shaping the immunological landscape and determining therapeutic responses will facilitate the improvement of current treatment modalities and the design of innovative strategies to precisely target CSCs.

Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4 + T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8 + T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.

Cyclophilin A (CypA), the cellular receptor of the immunosuppressant cyclosporin A (CsA), is an abundant cytosolic protein and is involved in a variety of diseases. For example, CypA supports cancer proliferation and mediates viral infections, such as the human immunodeficiency virus 1 (HIV-1). Here, we present the design of PROTAC (proteolysis targeting chimera) compounds against CypA to induce its intracellular proteolysis and to investigate their effect on immune cells. Interestingly, upon connecting to E3 ligase ligands, both peptide-based low-affinity binders and CsA-based high-affinity binders can degrade CypA at nM concentration in HeLa cells and fibroblast cells. As the immunosuppressive effect of CsA is not directly associated with the binding of CsA to CypA but the inhibition of phosphatase calcineurin by the CypA:CsA complex, we investigated whether a CsA-based PROTAC compound could induce CypA degradation without affecting the activation of immune cells. P3, the most efficient PROTAC compound discovered from this study, could deplete CypA in lymphocytes without affecting cell proliferation and cytokine production. This work demonstrates the feasibility of the PROTAC approach in depleting the abundant cellular protein CypA at low drug dosage without affecting immune cells, allowing us to investigate the potential therapeutic effects associated with the endogenous protein in the future.

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO T helper 1 cells and CD8 T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7 CD8 T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1 CD38 CD8 cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized.

Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma. TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete. Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5–34·8), 39 (36%, 90% CI 28–44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24–40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3–4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia. In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy. Bristol Myers Squibb.

The human mononuclear phagocytes system consists of dendritic cells (DCs), monocytes, and macrophages having different functions in bridging innate and adaptive immunity. Among the heterogeneous population of monocytes the cell surface marker slan (6-sulfo LacNAc) identifies a specific subset of human CD14 CD16 non-classical monocytes, called slan monocytes (slanMo). In this review we discuss the identity and functions of slanMo, their contributions to immune surveillance by pro-inflammatory cytokine production, and cross talk with T cells and NK cells. We also consider the role of slanMo in the regulation of chronic inflammatory diseases and cancer. Finally, we highlight unresolved questions that should be the focus of future research.

Cancer stem cells (CSCs) are pluripotent and highly tumorigenic cells that can re-populate a tumor and cause relapses even after initially successful therapy. As with tissue stem cells, CSCs possess enhanced DNA repair mechanisms. An active DNA damage response alleviates the increased oxidative and replicative stress and leads to therapy resistance. On the other hand, mutations in DNA repair genes cause genomic instability, therefore driving tumor evolution and developing highly aggressive CSC phenotypes. However, the role of DNA repair proteins in CSCs extends beyond the level of DNA damage. In recent years, more and more studies have reported the unexpected role of DNA repair proteins in the regulation of transcription, CSC signaling pathways, intracellular levels of reactive oxygen species (ROS), and epithelial–mesenchymal transition (EMT). Moreover, DNA damage signaling plays an essential role in the immune response towards tumor cells. Due to its high importance for the CSC phenotype and treatment resistance, the DNA damage response is a promising target for individualized therapies. Furthermore, understanding the dependence of CSC on DNA repair pathways can be therapeutically exploited to induce synthetic lethality and sensitize CSCs to anti-cancer therapies. This review discusses the different roles of DNA repair proteins in CSC maintenance and their potential as therapeutic targets.

Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61–76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24–42]; p=0·0049). The most common grade 3–4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. Bristol Myers Squibb.

Sensing of pathogens by pattern recognition receptors (PRR) is critical to initiate protective host defence reactions. However, activation of the immune system has to be carefully titrated to avoid tissue damage necessitating mechanisms to control and terminate PRR signalling. Dectin-1 is a PRR for fungal β-glucans on immune cells that is rapidly internalised after ligand-binding. Here, we demonstrate that pathogen recognition by the Dectin-1a isoform results in the formation of a stable receptor fragment devoid of the ligand binding domain. This fragment persists in phagosomal membranes and contributes to signal transduction which is terminated by the intramembrane proteases Signal Peptide Peptidase-like (SPPL) 2a and 2b. Consequently, immune cells lacking SPPL2b demonstrate increased anti-fungal ROS production, killing capacity and cytokine responses. The identified mechanism allows to uncouple the PRR signalling response from delivery of the pathogen to degradative compartments and identifies intramembrane proteases as part of a regulatory circuit to control anti-fungal immune responses. Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.