Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the ...breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC.
Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta.
Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval CI, 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved.
The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Anti‐programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD‐L1 in ...predicting responses of patients with gastric cancer to anti‐PD‐1/PD‐L1 immunotherapy is controversial. Some studies suggested that intra‐ and inter‐tumoral heterogeneity of PD‐L1 expression might explain the controversy. This study aimed to analyze the expression of PD‐L1, PD‐L2, and PD‐1 as well as CD8(+) T‐cell density in primary tumors and lymph nodes from patients with stage T1‐4N+M0 gastric adenocarcinoma to explore the heterogeneity of PD‐1 signaling pathway molecules.
Methods
In primary tumors and metastatic as well as non‐metastatic lymph nodes from patients with stage T1‐4N+M0 gastric adenocarcinoma, we detected PD‐L1 and PD‐L2 expression with immunohistochemistry. CD8(+) T‐cell density in primary tumors and PD‐1 expression on CD8(+) T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients’ overall survival and disease‐free survival.
Results
Among 119 eligible patients who had undergone surgical resection, the positive rate of PD‐L1 was higher in metastatic lymph nodes than in primary tumors (45.4% vs. 38.7%, P = 0.005); the positive rate of PD‐1 on CD8(+) T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor‐free lymph nodes (both P < 0.001). The intensity of PD‐1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor‐free lymph nodes from the same patient. Beside, the positive rate of PD‐L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD‐L1 expression, PD‐L2 expression, a low density of CD8(+) T cells in primary tumors, and PD‐1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.
Conclusion
The expression of PD‐L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stage T1‐4N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD‐L1 expression in previous studies.
Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. ...In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.
The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Cancer immunotherapies that train or stimulate the inherent immunological systems to recognize, attack, and eradicate tumor cells with minimal damage to healthy cells have demonstrated promising ...clinical responses in recent years. However, most of these immunotherapeutic strategies only benefit a small subset of patients and cause systemic autoimmune side effects in some patients. Immunogenic cell death (ICD)‐inducing modalities not only directly kill cancer cells but also induce antitumor immune responses against a broad spectrum of solid tumors. Such strategies for generating vaccine‐like functions could be used to stimulate a “cold” tumor microenvironment to become an immunogenic, “hot” tumor microenvironment, working in synergy with immunotherapies to increase patient response rates and lead to successful treatment outcomes. This Minireview will focus on nanoparticle‐based treatment modalities that can induce and enhance ICD to potentiate cancer immunotherapy.
Nanoparticle‐mediated immunogenic cell death directly kills cancer cells and induces antitumor immune responses. Such in situ vaccination strategies can be used to activate the tumor microenvironment to synergize with cancer immunotherapies to improve patient response rates and treatment outcomes.
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their ...underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
Lysosomes are membrane‐enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in ...controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal‐dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage‐response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.
Lysosomes mediate intracellular degradation through the action of lysosomal hydrolases. Lysosomal membrane permeabilization (LMP) results in translocation to the cytoplasm of the intraluminal contents and consequent lysosome‐dependent cell death.
Epidermal growth factor receptor (EGFR) mutation status was reported to be associated with programmed death-ligand 1 (PD-L1) expression. However, the molecular mechanism of PD-L1 regulation by EGFR ...activation and the potential clinical significance of blocking PD-1/PD-L1 in EGFR-mutant non–small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs) were largely unknown.
Western blot, real-time polymerase chain reaction, immunofluorescence, and flow cytometry were employed to explore the association between PD-L1 and EGFR activation. Then, we used EGFR-TKIs and downstream pathways inhibitors to clarify the detailed signaling pathway involved in PD-L1 regulation. Cell apoptosis, viability, and enzyme-linked immunosorbent assay test were used to study the immune suppression by EGFR activation and immune reactivation by EGFR-TKIs and/or PD-1 blocking in tumor cells and human peripheral blood mononuclear cells coculture system.
We found that EGFR activation by EGF stimulation, exon-19 deletions, and L858R mutation could induce PD-L1 expression. EGFR activation upregulated PD-L1 through p-ERK1/2/p-c-Jun but not through p-AKT/p-S6 pathway. PD-L1 mediated by EGFR activation could induce the apoptosis of T cells through PD-L1/PD-1 axis in tumor cells and peripheral blood mononuclear cells coculture system. Inhibiting EGFR by EGFR-TKIs could free the inhibition of T cells and enhance the production of interferon-γ. Synergistic tumor cell killing effects were not observed with EGFR-TKIs and anti-PD-1 antibody combination treatment in coculture system.
Our results imply that EGFR-TKIs could not only directly inhibit tumor cell viability but also indirectly enhance antitumor immunity through the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for EGFR-TKI sensitive patients, especially for EGFR-TKIs resistant NSCLC patients with EGFR mutation. Combination of EGFR-TKIs and anti-PD-1/PD-L1 antibodies treatment in NSCLC is not supported by the current study but warrant more studies to move into clinical practice.
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•Regulated cell death (RCD) refers to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines.•Apoptosis, autophagy-dependent cell death and necroptosis have ...many links to carcinogenesis.•Small-molecule compounds modulate some RCD pathways that are key for cancer therapy.•Targeting of RCD subroutines is a potential strategy for cancer drug discovery.
Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more ‘magic bullets’ that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.
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