In recent years, research on immunotherapy has made great progress. Currently, immunotherapy has made significant breakthrough, especially programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors (e.g, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab and Avelumab, etc.) have brought clinical benefits to patients with various pathological types of lung cancer, including squamous cell carcinoma, adenocarcinoma and small cell lung cancer. In this paper, the application value and current status of PD-1/PD-L1 checkpoint inhibitors in lung cancer were comprehensively analyzed by reviewing and interpreting representative clinical studies. Based on the results of various large-scale clinical trials results, the indications of immunotherapy in lung cancer have been continuously broadened, and the details of immunotherapy have also been constantly optimized. However, immunotherapy still faces many challenges, such as the selection of immune combination strategies, the exploration of biomarkers, the management of adverse events, the feasibility of application of driver gene mutation population and so on. In this article, we made a systematic review about the latest progress of PD-1/PD-L1 checkpoint inhibitors in lung cancer, in order to provide cutting-edge reference for the clinical workers.
.
Animals ; Antineoplastic Agents, Immunological ; therapeutic use ; B7-H1 Antigen ; antagonists & inhibitors ; genetics ; immunology ; Humans ; Immunotherapy ; Lung Neoplasms ; drug therapy ; genetics ; immunology ; Programmed Cell Death 1 Receptor ; antagonists & inhibitors ; genetics ; metabolism

Recent studies on T cell immunology have been instrumental in developing therapies to overcome cancer immune escape, and immune checkpoint inhibitors have emerged as one of the most promising therapeutic tools in advanced cancer patients. Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that modulate the effects of immune checkpoints. These include cytotoxic T lymphocyte antigen 4 and programmed cell death protein 1, which are co-inhibitory signals responsible for immune suppression. Despite their clinical benefits, ICPIs behave as general immune activators, exerting to several toxic effects called immune-related adverse events attributed to organ-specific inflammation. Here, we review ICPI toxicities, highlighting the importance of their early identification and proper management.
Adrenal Cortex Hormones ; Allergy and Immunology ; Antibodies, Monoclonal ; Cell Death ; CTLA-4 Antigen ; Humans ; Inflammation ; United Nations

Objective To investigate the expression and regulation of programmed cell death protein 1 (PD1), B lymphocyte and T lymphocyte attenuator (BTLA) in peripheral blood of patients with non-small cell lung cancer (NSCLC); to examine the correlation of the mRNA levels between PD and BTLA in NSCLC. Methods Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8⁺ T cells and γδ⁺ T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals. We compared the expression of PD1 and BTLA on the surfaces of γδ⁺ T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid. The correlations of PD1 and BTLA, as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform. Results The frequency of PD1 on the surfaces of CD8⁺ T cells was significantly higher than that of the γδT cells in both healthy controls (t=2.324, P=0.024) and NSCLC patients（t=2.498, P=0.015). The frequency of PD1 on CD8⁺ T cells, rather than on γδ⁺ T cells, was significantly upregulated in advanced NSCLC patients compared with that in healthy controls (t=4.829, P<0.001). The PD1⁺ BTLA⁺γδT cells of the healthy controls were significantly lower than that of the NSCLC patients (t=2.422, P=0.0185). No differences in percentage of PD1⁺γδ⁺ and BTLA⁺γδ⁺ T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment. PD1 was positively correlated with BTLA in both lung adenocarcinoma (r=0.54; P<0.05) and lung squamous cell carcinoma (r=0.78; P<0.05). Conclusions The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8⁺ T cells and γδT cells in advanced NSCLC, suggesting that these molecules were involved in regulating the inactivation of CD8⁺ T cells and γδ⁺ T cells, immune escape and tumor invasion.
Bone Neoplasms/secondary* ; CD8-Positive T-Lymphocytes ; Carcinoma, Non-Small-Cell Lung/immunology* ; Case-Control Studies ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Ligands ; Lung Neoplasms/immunology* ; Lymphocyte Subsets/immunology* ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor/metabolism* ; RNA, Messenger/metabolism* ; Receptors, Antigen, T-Cell, gamma-delta ; Receptors, Immunologic/metabolism*

Systemic lupus erythematous (SLE) is a systemic autoimmune disease with multi-organ inflammation caused by the production of pathogenic autoantibodies and immune complexes reflecting a global loss of tolerance. Lupus nephritis (LN) is present in approximately 60% of SLE patients and is considered a major predictor of a poor prognosis. To date, many studies utilizing genomics, transcriptomics, epigenetics, metabolomics, and microbiome have been conducted on a range of animal models and lupus patients to understand the pathogenesis of SLE and LN. Collectively, these studies support the concept that LN is caused by increased cell death, which has not been properly dealt with; abnormal innate immunity; hyperactive adaptive immunity; and genetic variants triggered by a range of environmental factors. This review summarizes the results from studies that contributed strongly to elucidating the pathogenesis of SLE and LN, highlighting the immunological and non-immunological mechanisms.
Adaptive Immunity ; Allergy and Immunology ; Antigen-Antibody Complex ; Apoptosis ; Autoantibodies ; Autoimmune Diseases ; Cell Death ; Epigenomics ; Genomics ; Humans ; Immunity, Innate ; Inflammation ; Lupus Nephritis* ; Lymphocytes ; Metabolomics ; Microbiota ; Models, Animal ; Prognosis ; Wolves*

Small cell lung cancer (SCLC), which accounts for about 15% of lung cancer cases, is an aggressive disease characterized by rapid growth and early widespread metastasis. Despite sensitive to chemotherapy and radiotherapy, SCLC is vulnerable to get resistant and has high recurrence rates. In recent years, immunotherapy has shown good antitumor activity, especially programmed death receptor-1/ligand-L1 (PD-1/L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) Checkpoint inhibitors have changed the pattern of tumor treatment, and SCLC has high immunogenicity, high mutation load and other favorable immune factors, so immuno-checkpoint inhibitors may become an important breakthrough in SCLC treatment. This article will briefly review the clinical research of immunotherapy for small cell lung cancer.
.
Humans ; Immunologic Factors ; genetics ; immunology ; Immunotherapy ; methods ; trends ; Lung Neoplasms ; genetics ; immunology ; therapy ; Programmed Cell Death 1 Receptor ; genetics ; immunology ; Small Cell Lung Carcinoma ; genetics ; immunology ; therapy

Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
Antibodies, Monoclonal ; immunology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; immunology ; therapeutic use ; B7-H1 Antigen ; antagonists & inhibitors ; immunology ; Humans ; Neoplasms ; drug therapy ; immunology ; pathology ; Programmed Cell Death 1 Receptor ; antagonists & inhibitors ; immunology ; Signal Transduction ; drug effects ; immunology ; T-Lymphocytes ; immunology

Interleukin (IL) 33, a member of the IL-1 superfamily, is an "alarmin" protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcepsilonRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis.
Adaptive Immunity* ; Allergy and Immunology ; Blood Vessels ; Cell Death ; Cystitis, Interstitial ; Cytokines ; Endothelial Cells ; Fibronectins ; Heparin ; Histamine ; Humans ; Immunity, Innate ; Immunoglobulin E ; Interleukin-1 ; Interleukins ; Laminin ; Mast Cells* ; Peptide Hydrolases ; Receptors, IgE ; Urinary Bladder ; Urology ; Vascular Cell Adhesion Molecule-1 ; Vitronectin

OBJECTIVETo study the roles of follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells in the pathogenesis of Henoch-Schönlein purpura (HSP) in children.

METHODSPeripheral blood samples were collected from 40 HSP children and 25 healthy controls. The percentages of Tfh and Tfr cells were measured by flow cytometry; the mRNA expression levels of Bcl-6, c-MAF, Blimp-1, and PD-1 in peripheral blood were measured by real-time polymerase chain reaction.

RESULTSCompared with the controls, the children with HSP had significantly increased percentage of Tfh cells and Tfh/Tfr ratio but a significantly reduced percentage of Tfr cells in the peripheral blood (P<0.05). Compared with the controls, the children with HSP had significantly increased mRNA expression of Bcl-6 and c-MAF but significantly reduced mRNA expression of Blimp-1 in CD4+ T cells (P<0.05), and had significantly increased mRNA expression of PD-1 but significantly reduced mRNA expression of Blimp-1 in CD4+CD25+ regulatory T cells (P<0.05).

CONCLUSIONSAbnormal percentages of Tfh and Tfr cells may be involved in the pathogenesis of HSP in children, and over-expression of Bcl-6, c-MAF, and PD-1 mRNA and inhibited expression of Blimp-1 mRNA may be considered as important reasons for abnormal percentages of Tfh and Tfr cells.

Adolescent ; Child ; DNA-Binding Proteins ; genetics ; Female ; Humans ; Male ; Programmed Cell Death 1 Receptor ; genetics ; Proto-Oncogene Proteins c-bcl-6 ; Proto-Oncogene Proteins c-maf ; genetics ; Purpura, Schoenlein-Henoch ; etiology ; immunology ; T-Lymphocytes, Helper-Inducer ; immunology ; T-Lymphocytes, Regulatory ; immunology

OBJECTIVETo investigate effect of CD4(+) CD25(+) Foxp3(+) Tregs in the treatment of autoimmune myositis (EAM) in mice and explore the possible mechanisms.

METHODSMouse models of EAM were divided randomly into model group and treatment group, and the latter received infusion of CD4(+) CD25(+) Foxp3(+) Tregs separated from normal mouse spleen by magnetic activated cell sorting. The changes of muscle pathology was observed, and the expression of PD-1 and CTLA-4 in spleen CD4(+) CD25(+) Foxp3(+) Tregs was analyzed using flow cytometry; peripheral blood IL-10 and TGF-β levels were tested using double antibody sandwich ELISA.

RESULTSCompare with the model group, the mice in the treatment group showed significantly reduced muscular inflammatory cell infiltration, increased blood levels of IL-10 and TGF-β (P<0.05), and increased expression of PD-1 and CTLA-4 in spleen CD4(+) CD25(+) Foxp3(+) Tregs (P<0.05).

CONCLUSIONCD4(+) CD25(+) Foxp3(+) Tregs reinfusion produces therapeutic effect in mice with EAM by increasing peripheral blood IL-10 and TGF-β levels and PD-1 and CTLA-4 expressions in spleen CD4(+) CD25(+) Foxp3(+) Tregs.

Animals ; Autoimmune Diseases ; immunology ; CTLA-4 Antigen ; metabolism ; Cell Separation ; Cell- and Tissue-Based Therapy ; Disease Models, Animal ; Flow Cytometry ; Interleukin-10 ; blood ; Mice ; Myositis ; immunology ; Programmed Cell Death 1 Receptor ; metabolism ; Spleen ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Transforming Growth Factor beta1 ; blood

PURPOSE: To evaluate tumor-specific immunity and define the mechanisms involved in the cryoimmunologic response, we compared the tumor control efficacy and immunologic responses of cryoablation with those of surgical excision in a tumor rechallenge model. MATERIALS AND METHODS: Sixty BALB/c mice with RENCA tumors that were generated in the left flank area underwent cryoablation or radical excision. The mice successfully treated were rechallenged with RENCA or an undifferentiated colon carcinoma cell line, CT26, in the contralateral right flank area. The recurrence rate after tumor rechallenge in each group was then observed. To assess the immunologic response of each treatment modality, fluorescent-activated cell sorting (FACS) analysis and a cytotoxicity assay using 51Cr release were performed. RESULTS: After reinoculation of the RENCA cells, the rate of tumor growth was significantly higher in the surgical excision group than in the cryoablation group (94.4% vs. 11.1%, p=0.001). In the cryoablation group, the tumor growth rate was significantly increased after rechallenge of CT26 cells compared with RENCA (94.1% vs. 11.1%, p=0.001). The cryoablation group showed an elevated CD3, CD4, CD8 T, and natural killer cell count in the FACS analysis and also showed significantly increased cytotoxicity in the 51Cr release assay compared with the excision group. CONCLUSIONS: These results showed that cryoablation, compared to surgical resection, was more effective in preventing tumor growth after rechallenge with RENCA cells and that this response was tumor-specific, because the CT26 cells did not have the same effect.
Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Renal Cell/*immunology/pathology/*surgery ; Cell Death ; Cryosurgery/*methods ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Kidney Neoplasms/*immunology/pathology/*surgery ; Lymphocyte Count ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice, Inbred BALB C ; Neoplasm Recurrence, Local/immunology ; Neoplasm Transplantation