Effect Of PD-1 Research Articles

Amelioration of experimental autoimmune encephalomyelitis by exogenous soluble PD-L1 is associated with restraining dendritic cell maturation and CCR7-mediated migration

Dendritic cells (DCs) orchestrate both immune activation and immune tolerance in multiple sclerosis (MS). Manipulating the phenotypes and functions of DCs to boost their tolerogenic potential is an appealing strategy for treating MS and its animal model experimental autoimmune encephalomyelitis (EAE). Programmed cell death 1 (PD-1) delivers the immunoinhibitory signals by interacting with PD-1 ligand 1 (PD-L1), which plays a critical role in maintaining immune tolerance. So far, the effects of PD-1/PD-L1 signalling activation on DCs in EAE are poorly understood. Here, the administration of soluble PD-L1 (sPD-L1) protein significantly alleviated the clinical symptoms of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, and inhibited the expression of cluster of differentiation (CD)86, C-C motif chemokine receptor 7 (CCR7) as well as CCR7-mediated trafficking of splenic DCs, accompanied by enhancing their phagocytosis. The impact of sPD-L1 on the surface morphology and mechanical properties of DCs was investigated at the nanoscale, using scanning electron microscope and atomic force microscope. The treatment of sPD-L1 was found to mitigate morphological maturation and biomechanical alterations, specifically in terms of adhesion and elasticity, in bone marrow-derived DCs from EAE. Taken together, our findings suggest that application of exogenous sPD-L1 has a marked suppressive effect on the maturation and migration of DCs in EAE. PD-L1 administration may be a promising therapy for EAE and for MS in the future.

Effect of PD-1/ PD-L1 and statin combination therapy on gastrointestinal toxicity related to immune checkpoint inhibitors and on survival.

742 Background: Immune Checkpoint Inhibitor (ICI) therapy has greatly expanded its approval to treat a variety of malignancies with high efficacy. Inhibitors of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are two of the most common classes of ICI therapy. There has been significant research into medications that may have a synergistic effect with ICI therapy, notably statins due to their pro-apoptotic effect. The addition of statins to immunotherapy may also increase the risk of developing certain immune related adverse events (irAEs). We sought to investigate the effect of statin use on the development of gastrointestinal (GI) irAEs and on survival of patients on PD-1/L1 therapy. Methods: We conducted a review of select cancer patients at a tertiary cancer center who received PD-1/L1 inhibitors and statins between 2016 and 2022. The clinical characteristics and overall survival were compared to a control group who received PD-1/L1 inhibitors without statins. Results: A total of 823 patients were included in the statin group and compared to 11101 patients in the control group. In the statin group 707 received a PD-1 inhibitor, 86 received a PD-L1 inhibitor, and 30 received both checkpoint inhibitors. The included cancer types were lung cancer (44%), kidney cancer (26%), head/neck cancer (19%), and GI cancer (7.0%). The overall incidence of GI irAEs in patients receiving statins was 10.8%, which was comparable to patients without statin treatment (11.1%, p=0.83). In addition, statin treatment appeared to be associated with a more favorable survival in patients overall (p= 0.004) and also those with GI irAEs (p=0.047). Conclusions: Synergism between statins and PD-1/L1 inhibitors continues to be a developing field of interest. Our data showed the combination therapy’s survival benefit without exacerbating GI toxicity, which warrants further investigation of this treatment strategy.

Identification and verification of PTPN3 as a novel biomarker in predicting cancer prognosis, immunity, and immunotherapeutic efficacy

BackgroundThe importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received widespread attention. Nevertheless, little is known about the biological roles of PTPN3 in drug sensitivity, immunotherapeutic effectiveness, tumor immune microenvironment, and cancer prognosis.MethodsThe Cancer Genome Atlas (TCGA) database's RNAseq data were used to examine the expression of PTPN3 in 33 different cancer types. In addition, immunohistochemistry (IHC) was performed to validate the expression of PTPN3 across various cancer types within our clinical cohorts. The features of PTPN3 alterations were demonstrated throughout the cBioPortal database. This study focused on examining the prognostic and clinicopathological importance of PTPN3 through the acquisition of clinical data from the TCGA database. The investigation of PTPN3's probable role in the tumor immune microenvironment was demonstrated by the application of CIBERSORT, ESTIMATE algorithms, and the TISIDB database. Using Spearman's rank correlation coefficient, the relationships between PTPN3 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) were evaluated. To further investigate the putative biological activities and downstream pathways of PTPN3 in various cancers in humans, Gene Set Enrichment Analysis (GSEA) was carried out. In addition, an examination was conducted to explore the associations between PTPN3 and the effectiveness of PD-1/PD-L1 inhibitors, utilizing data extracted from the GEO database.ResultsPTPN3 was abnormally expressed in multiple cancer types and was also strictly associated with the prognosis of cancer patients. IHC was used to investigate and confirm the various expression levels of PTPN3 in various malignancies, including breast cancer, lung cancer, sarcoma, and kidney renal clear cell carcinoma in our clinical cohorts. There is a high correlation between the levels of PTPN3 expression in different cancers and infiltrating immune cells, including mast cells, B cells, regulatory T cells, CD8 + T cells, macrophages, and dendritic cells. Infiltrating immune cells, such as regulatory T cells, CD8 + T cells, macrophages, B cells, dendritic cells, and mast cells, are strongly correlated with PTPN3 expression levels in various tumors. The expression of PTPN3 exhibited a substantial correlation with many immune-related biomolecules and the expression of TMB and MSI in multiple types of cancer. In addition, PTPN3 has demonstrated promise in predicting the therapeutic benefits of PD-1/PD-L1 inhibitors and the susceptibility to anti-cancer medications in the treatment of clinical cancer.ConclusionsOur findings highlight the importance of PTPN3 as a prognostic biomarker and predictor of immunotherapy success in various forms of cancer. Furthermore, PTPN3 appears to have an important role in modifying the tumor immune microenvironment, highlighting its potential as a promising biomarker for prognosis prediction, immunotherapeutic efficacy evaluation, and identification of immune-related characteristics in diverse cancer types.

Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion

BackgroundAdoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic...

The effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B cells and CD4+T cells in peripheral blood of patients with systemic lupus erythematosus

BackgroundThe defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail.MethodsPD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA.ResultsThe PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs.ConclusionsAxis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.

Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy.

The PD-1/PD-L1 signaling pathway plays a crucial role in cancer immune evasion, and the use of anti-PD-1/PD-L1 antibodies represents a significant milestone in cancer immunotherapy. However, the low response rate observed in unselected patients and the development of therapeutic resistance remain major obstacles to their clinical application. Accumulating studies showed that overexpressed TGF-β is another immunosuppressive factor apart from traditional immune checkpoints. Actually, the effects of PD-1 and TGF-β pathways are independent and interactive, which work together contributing to the immune evasion of cancer cell. It has been verified that blocking TGF-β and PD-L1 simultaneously could enhance the efficacy of PD-L1 monoclonal antibody and overcome its treatment resistance. Based on the bispecific antibody or fusion protein technology, multiple bispecific and bifunctional antibodies have been developed. In the preclinical and clinical studies, these updated antibodies exhibited potent anti-tumor activity, superior to anti-PD-1/PD-L1 monotherapies. In the review, we summarized the advances of bispecific antibodies targeting TGF-β and PD-L1 in cancer immunotherapy. We believe these next-generation immune checkpoint inhibitors would substantially alter the cancer treatment paradigm, especially in anti-PD-1/PD-L1-resistant patients.

Effect of PD-1 Inhibitor on PI3K/AKT Pathway in Tumor Cell and TCell Activity in Non-small Cell lung Cancer (NSCLC)

Lung cancer is one of the most lethal cancers around the world and non-small cell lung cancer takes up about 85% ofthe cases. PD-1 inhibitor is an antibody used in immunotherapy to treat cancer. Previous studies have reported thatthe PD-1 inhibitor can block the PD-1/PD-L1 binding and help the immune system recognize and attack tumors. ThePI3K/AKT signaling pathway is an important target of the PD-1 downstream pathway. This paper studies the effects ofPD-1 inhibitor Pembrolizumab on the activation of the PI3K/AKT pathway in vivo. In this study, A549 cell line willbe used as the non-small cell lung cancer model. The immune-deficient mice will be injected with Keytruda, saline(negative control) or Taxol (positive control). Flow cytometry and Western Blot will be used to measure the activationof tumor cells and CD4 T cells. This paper investigates whether or not PD-1 inhibitor would effectively block thePI3K/AKT pathway and increase T cell proliferation. The result of this study will explore the blocking mechanism ofPembrolizumab on PI3K/AKT pathway. Future studies should focus on the acquired resistance caused by mutations andits effects on PD-1 inhibitor treatment with PI3K/AKT pathway activation as the biomarker.

Incidence risk of peripheral edema in cancer patients treated with PD-1/PD-L1 inhibitors: A PRISMA guideline systematic review and meta-analysis.

To elucidate the relationship between peripheral edema and programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, the meta-analysis was performed. Following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses, all-grade and grade 3-5 of peripheral edema data extracted from clinical trials were taken into account for the final comprehensive assessments. Twenty-seven PD-1/PD-L1-related clinical trials with peripheral edema data were collected. Compared with chemotherapy (PD-1/PD-L1 vs chemotherapy), the risk of developing peripheral edema for all-grade was much lower (odds ratio [OR] = 0.36, 95% confidence interval [CI]: [0.23, 0.56], Z = 4.55 [P < .00001]). When PD-1/PD-L1 plus chemotherapy were compared with chemotherapy, no significant analysis results for all-grade was found (OR = 1.15, 95% CI:[0.93, 1.44], I2 = 25%, Z = 1.27 [P = .20]). Similar risk trends could also be found when the incidence risk of peripheral edema for grade 3-5 was evaluated. No obvious publication bias was identified throughout the total analysis process. The effect of PD-1/PD-L1 inhibitor on the risk of developing peripheral edema was weaker than that of chemotherapy, and the combination with chemotherapy slightly increased the incidence risk of developing peripheral edema without statistical significance.

Current progress and future perspectives of neoadjuvant anti-PD-1/PD-L1 therapy for colorectal cancer.

Immunotherapies, especially the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, have revolutionized the therapeutic strategies of various cancers. As for colorectal cancer (CRC), the current clinical application of PD-1/PD-L1 inhibitors are mainly used according to the mutation pattern, which is categorized into deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) and proficient mismatch repair (pMMR), or non-high levels of microsatellite instability (non-MSI-H). PD-1/PD-L1 inhibitors have been proven to have favorable outcomes against dMMR/MSI-H CRC because of more T-cell infiltration into tumor tissues. Nevertheless, the effectiveness of PD-1/PD-L1 inhibitors in pMMR/non-MSI-H CRC is still uncertain. Because of the quite-lower proportion of dMMR/MSI-H in CRC, PD-1/PD-L1 inhibitors have been reported to combine with other antitumor treatments including chemotherapy, radiotherapy, and targeted therapy for better therapeutic effect in recent clinical trials. Neoadjuvant therapy, mainly including chemotherapy and radiotherapy, not only can reduce clinical stage but also benefit from local control, which can improve clinical symptoms and the quality of life. Adding immunotherapy into neoadjuvant therapy may change the treatment strategy of primary resectable or some metastatic CRC. In this review, we focus on the development of neoadjuvant anti-PD-1/PD-L1 therapy and discuss the future perspectives in CRC.

The role of PD-1/PD-L1 inhibitors in the treatment for non-small cell lung cancer (NSCLC)

Non-small cell lung cancer (NSCLC) is a frequent cancer that affects people around the world. Checkpoint inhibitors are the most intensively studied treatment methods at present. Activation of PD-1/PD-L1 is accountable for suppressing the activation, proliferation, and cytotoxic secretion of T cells. By giving PD-1 /PD-L1 inhibitors, an individual's immune system can be boosted to some extent. Nivolumab, pembrolizumab, atezolizumab, and durvalumab have shown to be effective for NSCLC patients in clinical trials. The effectiveness of PD-1/PD-L1 inhibitors combining with SBRT, chemotherapy, or other checkpoint inhibitors to treat NSCLC has also been demonstrated. However, PD-1/PD-L1 inhibitors also have drawbacks, such as non-specific recognition misses, and immune-related adverse events. This article mainly discusses the role of PD-1/PD-L1 inhibitors in the treatment for NSCLC.

Metabolism of tryptophan in non-small lung cancer patients with different effect of PD-1 / PD-L1 inhibitors immunotherapy

Introduction. In the structure of cancer incidence, lung cancer ranks first among men. In order to study the molecular mechanisms of the initiation and progression of lung cancer, it is necessary to study not only the tumor cells themselves, but also the features of the systemic tryptophan metabolism. Tryptophan catabolites, being to a large extent product of the metabolic activity of the intestinal microbiota, can affect the effectiveness of immunotherapy with checkpoint inhibitors. The kynurenine pathway of tryptophan metabolism is intensified in the body of cancer patients; its products have a pro-oncogenic and immunosuppressive effect, which may hinder the effectiveness of immunotherapy.Objective – to study the dynamics of changes in various metabolites of tryptophan metabolism in the blood serum and feces of patients with non-small cell lung cancer with various effects of immunotherapy with inhibitors of PD-1 (programmed cell death receptor 1) / PD-L1 (programmed cell death receptor 1 ligand).Materials and methods. The study included blood serum and stool samples obtained from 20 patients with non-small cell lung cancer treated with PD-1 / PD-L1 inhibitors. Using high-performance liquid chromatography with mass spectrometric analysis, the levels of 13 tryptophan metabolites were assessed in patients with various effects of immunotherapy. The significance of differences between the samples was assessed using a nonparametric method according to the Mann – Whitney test. They were considered statistically significant at p &lt;0.05.Results. In fecal analyzes of patients in whom a positive effect of immunotherapy was observed, baseline levels of 5-hydroxyindole acetate and quinolinic acid were lower than in patients with tumor progression. Positive clinical dynamics was accompanied by a decrease in the content of indole-3-lactate, kynurenine and indole-3-carboxaldehyde in the feces of patients. In the serum of patients with a positive response, the initial content of 5-hydroxyindole acetate, indole-3-acetate, indole-3-butyrate and quinoline acid was lower than in patients with progression of non-small cell lung cancer. A positive response to immunotherapy was characterized by an increase in the levels of indole-3-butyrate and indole-3-propionate, and a negative response was not accompanied by statistically significant changes in the studied tryptophan metabolites.Conclusion. Profiling tryptophan metabolites in feces and serum of patients with non-small cell lung cancer can be used to predict the effectiveness of immunotherapy with PD-1 / PD-L1 inhibitors.

Combining stereotactic radiotherapy with anti-PD-1 for advanced hepatocellular carcinoma patients with portal vein tumor thrombus.

e16121 Background: Immunotherapy has attracted extensive attention in advanced hepatocellular carcinoma. For unselected patients, the efficacy of PD-1 monotherapy is less than 20%. The addition of radiotherapy to local lesions can significantly enhance the effectiveness of PD-1. However, the efficiency of SBRT combined with PD-1 in the treatment for portal vein tumor thrombus in patients with hepatocellular carcinoma remains unclear. Methods: This phase II study enrolled 17 patients with advanced liver cancer with portal vein tumor thrombus after 1-line or multi-line treatment in our single center, between June 2018 and June 2021. SBRT was delivered to the carcinoma thrombus with or without primary intrahepatic tumor，with a median total dose of 60Gy/10fx (range of 50Gỹ70Gy). Camrelizumab was administered within 2 weeks after SBRT, in cycles of every 3 weeks, until disease progression or patient intolerance. The primary endpoints were overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Results: At 3 months after SBRT, 6 patients had complete responses (35.3%) and 11 patients had partial responses (64.7%), with an ORR of 100%. The 1-year OS rate was 100%, and 1-year PFS was 84.8%. None of the patients had radiation response. Four patients (23.5%) were unable to tolerate immunotherapy, with one patient stopping after 12 cycles due to frequent preventricular phase contraction (in a double couplet rhythm) and 3 owing to upper gastrointestinal bleeding. Conclusions: SBRT combined with immunotherapy can improve local control and bring survival benefit, suggesting that SBRT could be considered in patients with portal vein tumor thrombus in hepatocellular carcinoma after 1-line or multi-line treatment. Moreover, the adverse reactions were mild. Clinical trial information: ChiCTR1900026188.

Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses

SUMMARYDual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT’s ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.

A phase Ib/II study (IMMCO-1) of atezolizumab plus tivozanib in castrate-resistant prostate cancer and certain other immunologically cold tumors.

TPS208 Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The tivozanib dose will be determined via a 3+3 dose de-escalation phase Ib portion. Patients treated in the phase Ib portion will be included as study subjects for phase the II portion. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of &lt;7% (one-sided alpha = 0.05; 80% power). A Simon’s two-stage design will be utilized and if ≥2 responses among the first 16 evaluable patients, a further 10 evaluable patients will be accrued for a total of 26. Up to 33 subjects will be enrolled to account for a 20% dropout rate. The null hypothesis will be rejected if at least 5 responses are observed. The University of Florida's Data Integrity and Safety Committee will review significant adverse events. Tivozanib will be given at a dose of 1.34 mg/day for 21 days of each 28-day cycle (potential dose reduction is to 0.89 mg/day). Atezolizumab is given at a dose of 1,680 mg every 28 days. Treatment is until disease progression or intolerance. Key inclusion criteria include a diagnosis of certain advanced and unresectable or metastatic immunologically cold tumors (CRPC previously treated with an androgen inhibitor or cytotoxic chemotherapy in the advanced or metastatic setting, bile duct or gallbladder cancer, certain HR-negative HER2-positive breast cancers, ovarian cancer, pancreatic adenocarcinoma, soft tissue sarcoma, or vulvar cancer), at least one prior systemic therapy in this setting, ECOG 0-1 (phase Ib) or ECOG 0-2 (phase II), age ≥ 18, adequate hematologic and end-organ function, life expectancy of at least 12 weeks, and measurable disease by RECIST v1.1. Key exclusion criteria include known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. Active enrollment continues. Clinical trial information: NCT05000294.

Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

Several clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

Unbalanced expression of membrane-bound and soluble programmed cell death 1 and programmed cell death ligand 1 in systemic juvenile idiopathic arthritis

The study aimed to investigate the soluble programmed death-1 (sPD-1) and its ligand (sPD-L1) levels in systemic juvenile idiopathic arthritis (sJIA) patients and elucidate its underlying immunomodulatory mechanisms. Plasma levels of sPD-1, sPD-L1 and related cytokines and proteins were detected using an enzyme-linked immunosorbent assay (ELISA) and Luminex. The effects of PD-1/PD-L1 signal on mDC (myeloid dendritic cell) and IL-6 secretion were measured using flow cytometry. The results revealed decreased levels of sPD-1 in sJIA patients negatively correlated with JADAS-27, PGA, PtGA and CRP. sJIA patients had lower CD86 and MHC-II expression on mDC. When blocking PD-1/PD-L1 signal, IL-6 secretion of DC were increased. Our finding displayed downregulated sPD-1 was related with clinical indicators and could be a new biomarker for sJIA diagnosis. The reduced membrane and soluble forms of PD-1/PD-L1 might take part in sJIA pathogenesis by enhancing mDC proliferation and IL-6 secretion.

PD-1 Mediates Lineage Fate Determination and Function of Myeloid Cells in Response to Tumor-Mediated “Emergency” Myelopoiesis

PD-1 is an inhibitory receptor for which blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of how PD-1 compromises anti-tumor function and how such effect is reversed by PD-1 blockade remain poorly understood. The rapid change in hematopoietic output that occurs in response to immunologic stress is known as “emergency” myelopoiesis. This process is co-opted by tumors to evade the immune system by inducing potent immunosuppression. Cancer-driven granulo-monocytopoiesis modifies the composition of the hematopoietic output by stimulating the expansion of tumor promoting immature myeloid populations, defined as myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Monocytic (M-) and granulocytic (PMN-) MDSCs and TAMs differentiate from granulocyte/macrophage progenitors (GMP) in the bone marrow. We analyzed the myeloid compartment of tumor-bearing mice to determine the expression and function of PD-1 in myeloid cells during cancer-driven emergency myelopoiesis. Using three different mouse tumor models (MC38, B16 and MC17), we determined that PD-1 and its natural ligand PD-L1, were expressed at high levels in all subsets of myeloid cells isolated from the spleen of tumor-bearing mice, including CD11b+Ly6C+ M-MDSC, CD11b+Ly6G+ PMN-MDSC, CD11b+F/480+ macrophages and CD11b+HLA-DR+ dendritic cells (DC). This was in contrast to the significantly lower or undetectable levels of PD-1 expressed in these cellular counterparts isolated from non-tumor bearing mice. High expression of PD-1 and PD-L1 was also identified in these myeloid subsets isolated from the tumor site and at sites of secondary myelopoiesis in the gut. Because these myeloid cell populations differentiate from GMP upon cancer-mediated emergency myelopoiesis, we examined bone marrow myeloid progenitors in tumor bearing and control, non-tumor bearing mice. In non-tumor bearing mice, PD-1 was detected in Lin-/Sca+/Kit+ (LSK) myeloid progenitors, whereas PD-L1 was expressed in Lin-/Sca-/Kit+ (LK), common myeloid progenitors (CMP) and GMP. In tumor-bearing mice, both PD-1 and PD-L1 expression was significantly higher in all myeloid progenitors compared to tumor-free control mice. To determine whether PD-1-mediated signaling in myeloid cells might affect the magnitude and composition of the myeloid output that is altered by cancer-mediated emergency response, we used PD-1 deficient mice. PD-1 ablation, which decreased tumor growth and metastasis, stimulated the differentiation of hematopoietic progenitor cells and resulted in increase of Ly6Chi monocytes and monocyte-derived DC (mo-DC). Abrogation of PD-1 signaling enhanced the maturation of MDSCs by inducing the lineage commitment transcription factors IRF8, IRF4 and RORC1. IRF8 and IRF4 promote monocyte/macrophage and hinder granulocyte differentiation, whereas RORC1 is required for expansion of Ly6Chi monocytes and resolution of inflammation. To examine whether the effects of PD-1 on cancer-mediated emergency myelopoiesis and on myeloid lineage commitment and differentiation were mediated by myeloid cell-intrinsic mechanisms, we generated mice with conditional targeting of the PD-1 gene in the myeloid compartment by crossing PD-1fl/fl with LysM-Cre mice. Myeloid-specific ablation of PD-1 signaling in PD-1fl/fl/LysM-Cre mice impaired tumor growth to a similar extent as global PD-1 ablation in PD1-KO mice and induced a myeloid cell fate switch from MDSCs to effector-like myeloid cells that could be identified in spleen and tumor. Further, abrogation of PD-1 signaling in the myeloid compartment prevented the expansion of tumor-stress associated GMP in PD-1fl/fl/LysM-Cre mice and resulted in increased differentiation of committed monocyte progenitors (CMOP) and monocyte progenitors (MP) in the bone marrow. Moreover, PD-1 deletion significantly diminished NO production by M-MDSC and reversed their ability to suppress antigen-specific T cell responses. Our results reveal a previously unidentified role of the PD-1:PD-L1 pathway in the differentiation of lineage-committed myeloid progenitors during tumor-mediated emergency myelopoiesis to promote MDSCs and suppress effector monocytes and mo-DCs. Switch of myeloid progenitor fate commitment might be a key mechanism by which PD-1 blockade mediates its anti-tumor function. DisclosuresNo relevant conflicts of interest to declare.

Functional characterization of PD1+TIM3+ tumor-infiltrating T cells in DLBCL and effects of PD1 or TIM3 blockade

In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell–like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies.

Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer.

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China

BackgroundProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors are increasingly used in China, but no real-world data are available about the immune-related adverse events (irAEs). This real-world retrospective study aimed to assess the safety and effectiveness of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC) and to analyze the association between irAEs and effectiveness.MethodsThis was a retrospective study of the clinical data of patients with NSCLC treated with PD-1/PD-L1 inhibitors from August 2016 to November 2019 at Beijing Cancer Hospital. The patients were divided into the irAE or non-irAE groups. Overall adverse events, the impact of irAE on tumor response, and the association of irAEs with effectiveness were evaluated.ResultsOne hundred and ninety-one patients were included, including 70 (36.6%) patients in the irAE group and 121 (63.4%) patients in the non-irAE group. AE, grades 3–5 AEs, and irAE occurred in 107 (56.0%), 24 (12.6%), and 70 (36.6%) of the patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were higher in the irAE group compared with the non-irAE group (42.0% vs. 25.8%, P=0.038; 91.9% vs. 70.8%, P=0.002). Multivariable analyses identified that irAE were associated with progression-free survival (HR=0.62, 95%CI: 0.43–0.91; P=0.015), but not with overall survival (HR=0.76, 95%CI: 0.44–1.28; P=0.299).ConclusionIn NSCLC treated with PD-1/PD-L1 inhibitors, patients with irAEs showed improved effectiveness over patients without irAEs. Future studies of anti-PD-1/PD-L1 immunotherapy should explore this association and the underlying biological mechanisms of efficacy.