Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map ...the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC.
Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen‐4 (CTLA‐4), programmed cell death ligand‐1 (PD‐L1) and programmed cell ...death‐1 (PD‐1). Immunotherapy targeting the PD‐1/PD‐L1 checkpoints has shown promising efficacy in non‐small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte‐activation gene‐3 (LAG‐3) is another vital checkpoint that may have a synergistic interaction with PD‐1/PD‐L1. Here we review the LAG‐3 function in cancer, clinical trials with agents targeting LAG‐3 and the correlation of LAG‐3 with other checkpoints.
Immunotherapy in cancer is a hot topic and many oncologists want to learn about the relevant biomarkers with the current focus on CTLA 4 and PD 1/PD L1. However, also of interests are the varieties of alternative immune checkpoints including Lag 3/MHC II. In this paper, we review LAG 3 structure, function, the synergistic effects with CTLA 4 and PD 1/PD L1, as well as discussing LAG 3 clinical trials which are ongoing.
Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for ...cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy.
Immunotherapy that targets checkpoints, especially programmed cell death protein 1 and programmed cell death ligand 1, has revolutionized cancer therapy regimens. The overall response rate to ...mono-immunotherapy, however, is limited, emphasizing the need to potentiate the efficacy of these regimens. The functions of immune cells are modulated by multiple stimulatory and inhibitory molecules, including lymphocyte activation gene 3 (LAG-3). LAG-3 is co-expressed together with other inhibitory checkpoints and plays key roles in immune suppression. Increasing evidence, particularly in the last 5 years, has shown the potential of LAG-3 blockade in anti-tumor immunity. This review provides an update on the biological properties and clinical applications of LAG-3 in cancers.
Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, ...upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.
This review summarizes basic knowledge of DNA damage response (DDR) pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and its potential applications as therapeutic targets in cancer immunotherapy. Display omitted
With a 5-year overall survival of approximately 20%, lung cancer has always been the number one cancer-specific killer all over the world. As a fusion of positron emission computed tomography (PET) ...and computed tomography (CT), PET/CT has revolutionized cancer imaging over the past 20 years. In this review, we focused on the optimization of the function of
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F-flurodeoxyglucose (FDG)-PET/CT in diagnosis, prognostic prediction and therapy management of lung cancers by computer programs. FDG-PET/CT has demonstrated a surprising role in development of therapeutic biomarkers, prediction of therapeutic responses and long-term survival, which could be conducive to solving existing dilemmas. Meanwhile, novel tracers and optimized procedures are also developed to control the quality and improve the effect of PET/CT. With the continuous development of some new imaging agents and their clinical applications, application value of PET/CT has broad prospects in this area.
Patients with malignant tumor treated with immunotherapy have received significant clinical benefits over the years. Immune checkpoint blocking agents, such as anti-cytotoxic T-lymphocyte-associated ...protein-4 (anti-CTLA-4) and anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibodies, have produced impressive clinical results in different types of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3), another immune checkpoint, could inhibit cancer immunity. Recent studies have highlighted that TIM-3 has an important role to play in T-cell exhaustion and correlates with the outcome of anti-PD-1 therapy. Targeting TIM-3 might be a promising approach for cancer immunotherapy. Here, we review the role of TIM-3 in cancer and clinical trials with TIM-3 inhibitors.
Abstract Background and purpose With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its ...acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI. Methods EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI. Result MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline ( p < 0.01). Conclusion miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3K/Akt pathway.
As a consequence of the improvements in diagnostic technology along with gains in life expectancy of cancer patients, the incidence of spine metastases has increased. Spine metastases can affect the ...patient’s quality of life and negatively impact on their prognosis. Multidisciplinary treatments involve surgery, chemotherapy, radiosurgery and radiotherapy. Spine metastases should be treated using a multidisciplinary and integrated approach that involves spinal surgeons, medical oncologists and radiologists. More research is required to elucidate the pathological mechanisms involved in the aetiology of spine metastasis. This review describes the current situation regarding the diagnosis of spine metastasis, what is understood about the pathological development of spine metastasis and the evolution of the multidisciplinary treatments that are available for patients with spine metastases.
Abstract
Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high ...heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression;
n
= 36), SCLC-N (high NEUROD1 expression;
n
= 32), SCLC-P (high POU2F3 expression;
n
= 14), and SCLC-Y (high YAP1 expression;
n
= 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (
p
< 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.
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