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The immune system detects disturbances in homeostasis that occur during infection, sterile tissue damage and cancer. This initiates immune responses that seek to eliminate the trigger of immune activation and to re-establish homeostasis. At the same time, these mechanisms can also play a crucial role in the progression of disease. The occurrence of DNA in the cytosol constitutes a potent trigger for the innate immune system, governing the production of key inflammatory cytokines such as type I interferons and IL-1β. More recently, it has become clear that cytosolic DNA also triggers other biological responses, including various forms of programmed cell death. In this article, we review the emerging literature on the pathways governing DNA-stimulated cell death and the current knowledge on how these processes shape immune responses to exogenous and endogenous challenges.This Review explains how innate sensors of DNA activate different types of programmed cell death. The authors consider the relevance of these cell death pathways during infection and in inflammatory diseases.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor. Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.

Background Current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents. Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations. Methods Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts. Results We report that an ICD process can be activated without the use of pharmacological compounds. We show that in Kras-mut/TP53-mut colorectal cancer cells the 15 kDa βGBP cytokine, a T cell effector with onco-suppressor properties and a potential role in cancer immunosurveillance, induces key canonical events required for ICD induction. We document ER stress, autophagy that extends from cancer cells to the corresponding xenograft tumours, CRT cell surface shifting, ATP release and evidence of dendritic cell activation, a process required for priming cytotoxic T cells into a specific anticancer immunogenic response. Conclusions Our findings provide experimental evidence for a rationale to explore a strategy based on the use of an immunomolecule that as a single agent couples oncosuppression with the activation of procedures necessary for the induction of long term response to cancer.

PD-1, a negative coreceptor expressed on antigen-stimulated T cells and B cells, seems to serve as a 'rheostat' of the immune response. The molecular mechanisms of the functions of PD-1, in conjunction with the mild, chronic and strain-specific autoimmune phenotypes of PD-1-deficient mice, in contrast to the devastating fatal autoimmune disease of mice deficient in the immunomodulatory receptor CTLA-4, suggest that immunoregulation by PD-1 is rather antigen specific and is mainly cell intrinsic. Such unique properties make PD-1 a powerful target for immunological therapy, with highly effective clinical applications for cancer treatment.

Paclitaxel (PTX) has shown pleiotropic immunologic effects on the tumor microenvironment, and nanomicelle has emerged as a promising strategy for PTX delivery. However, the detailed mechanisms remain to be fully elucidated. Meanwhile, immunogenic cell death (ICD) is an effective approach to activate the immune system. This study investigated the ICD effect of PTX and how nanomicelle affected the immune-activation ability of PTX. The ICD effects of PTX were identified via the expression of ICD markers and cell vaccine experiment. Tumor size and overall survival in multiple animal models with treatment were monitored to evaluate the antitumor effects. The mechanisms of PTX-induced ICD and antitumor immunity were determined by detecting gene expression related to ER stress and analyzing immune cell profile in tumor after treatment. We revealed the immune-regulation mechanism of PTX nanomicelle by inducing ICD, which can promote antigen presentation by dendritic cells (DCs) and activate antitumor immunity. Notably, nanomicelle encapsulation protected the ICD effects and immune activation, which were hampered by immune system impairment caused by chemotherapy. Compared with traditional formulations, a low dose of nanomicelle-encapsulated PTX (nano-PTX) treatment induced immune-dependent tumor control, which increased the infiltration and function of both T cells and DCs within tumors. However, this antitumor immunity was hampered by highly expressed PD-1 on tumor-infiltrating CD8 T cells and upregulated PD-L1 on both immune cells and tumor cells after nano-PTX treatment. Combination therapy with a low dose of nano-PTX and PD-1 antibodies elicited CD8 T cell-dependent antitumor immunity and remarkably improved the therapeutic efficacy. Our results provide systemic insights into the immune-regulation ability of PTX to induce ICD, which acts as an inducer of endogenous vaccines through ICD effects, and also provides an experimental basis for clinical combination therapy with nano-PTX and PD-1 antibodies.

Immunotherapy has transformed cancer treatment, including early triple-negative breast cancer (TNBC), yet most patients with advanced TNBC fail to respond to immune checkpoint blockade (ICB) plus chemotherapy. Durable control likely requires not only tumour cell killing but also immunogenic cell death (ICD) that activates antitumour immunity. Using a Brca1 ⁻/⁻ p53 ⁻/⁻ organoid-derived TNBC model that recapitulates the immune landscapes of basal-like tumours, we show that RIPK1-driven ICD synergises with anti-PD-1 therapy to induce durable tumour control and immune memory in immune-infiltrated tumours. Mechanistically, both tumour-intrinsic and stromal necroptosis are required. Deletion of Ripk1 or Mlkl in tumour cells, or Mlkl in the stromal compartment, markedly impairs therapeutic efficacy. Moreover, immunologically “cold” tumours can be rendered responsive to ICD-based therapy by STING agonists. These findings demonstrate that the benefit of IAP antagonism with checkpoint blockade critically depends on coordinated necroptosis in both tumour and stromal cells, underscoring the need to integrate tumour microenvironmental context when designing ICD-targeted immunotherapies. Most advanced triple-negative breast cancers remain resistant to immunotherapy. Here, the authors discover that RIPK1-driven necroptosis in both tumor and stromal compartments is essential for effective immunogenic cell death-based therapy and immune checkpoint blockade.

BACKGROUNDThe anti-programmed cell death 1 (anti-PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of patients with advanced NSCLC, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC.METHODSIn total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or higher were randomly allocated to group A (n = 55 patients given pembrolizumab plus NK cells) or group B (n = 54 patients given pembrolizumab alone). The patients received i.v. pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received 2 cycles of NK cell therapy as 1 course of treatment.RESULTSIn our study, patients in group A had longer survival than did patients in group B (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months; P < 0.05). In group A patients with a TPS of 50% or higher, the median OS and PFS was significantly longer. Moreover, the patients in group A treated with multiple courses of NK cell infusion had better OS (18.5 months) than did those who received a single course of NK cell infusion (13.5 months).CONCLUSIONPembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1+ advanced NSCLC.TRIAL REGISTRATIONClinicalTrials.gov NCT02843204.FUNDINGThis work was supported by grants from the National Natural Science Foundation of China (NSFC) - Guangdong Joint Foundation of China (no. U1601225); the NSFC (no. 81671965); the Guangdong Provincial Key Laboratory Construction Project of China (no. 2017B030314034); and the Key Scientific and Technological Program of Guangzhou City (no. 201607020016).

Most clinically applied cancer immunotherapies rely on the ability of CD8 + cytolytic T cells to directly recognize and kill tumour cells 1 – 3 . These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment 4 – 6 . The ability of CD4 + effector cells to contribute to antitumour immunity independently of CD8 + T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified 7 – 10 . Here, we describe a mechanism whereby a small number of CD4 + T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting. The CD4 + effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II + CD11c + antigen-presenting cells. We show that T helper type 1 cell-directed CD4 + T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4 + T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4 + T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8 + T cells and natural killer cells and advance cancer immunotherapies. This article describes a mechanism through which CD4 + T cells can eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting and thereby complement the activity of CD8 + T cells and natural killer cells to advance cancer immunotherapies.

Background LGALS3BP, also referred as Gal-3BP, Mac2-BP, or 90 K, is a heavily glycosylated, secreted protein prominently localized at the surface of cancer-derived extracellular vesicles (EVs). Its levels are significantly elevated in various types of cancer, including neuroblastoma, and are generally associated with advanced disease and tumor progression. Our previous research has shown that LGALS3BP is an effective target for ravtansine (DM4)-based Antibody-Drug Conjugate (ADC) therapy in multiple preclinical models. Methods We assessed total and extracellular vesicles (EVs)-associated LGALS3BP through ELISA assay in serum of a pseudometastatic neuroblastoma model to evaluate the correlation of LGALS3BP levels with tumor dissemination. We employed a syngeneic neuroblastoma mouse model using murine neuroblastoma NXS2 cells overexpressing human LGALS3BP in order to evaluate immunogenic cell death (ICD) induced by anti-LGALS3BP ADC therapy and investigated the nature of the tumor immune infiltrate by cytofluorimetry. Furthermore, we designed a six-arm in vivo experiment to evaluate the efficacy of ADC in combination with an immune check-point inhibitor (ICI) anti-PD-1. Finally, a rechallenge assay was conducted on cured mice to assess the presence of immunological memory. Results Here, we report that circulating and EVs-associated LGALS3BP levels significantly correlate with neuroblastoma progression and dissemination. Moreover, we show that in the syngeneic NXS2 neuroblastoma model, DM4 treatment induces cell surface expression of ICD markers calreticulin, HSP70, and HSP90, and an increased PD-L1 expression in vitro, followed by enhanced tumor-infiltrating lymphocytes in vivo. Notably, the combination therapy of anti-LGALS3BP-targeting ADC with anti-PD-1 results in a higher inhibition of tumor growth and prolonged survival compared with either agent given alone. Rechallenge assay reveals that mice previously treated and cured with the ADC retain immune memory, suggesting the therapy’s ability to induce a durable and protective antitumor immune response. Conclusions Our findings establish that circulating LGALS3BP is a potential biomarker for liquid biopsy and uncover this protein as a suitable target for therapeutic strategies combining 1959-sss/DM4 ADC with an anti-PD-1 ICI for the treatment of LGALS3BP expressing neuroblastoma.

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma 1 , 2 , with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy 2 . The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17% 2 . Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features ( n  = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease 3 – 5 . The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities ( n  = 4), hepatitis and colitis ( n  = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery ( n  = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.