Immune Checkpoint Blockers Research Articles

HiJAKing Immunotherapy-Resistant Melanoma for a Cure.

Immune checkpoint blockers (ICBs) have brought great promise to patients with advanced melanoma, a tumor type that was claimed largely incurable not long ago. However, therapeutic resistance to ICBs has limited their utility in the clinic. Here, we provide a commentary on recent research endeavors concerning ICB resistance in melanoma patients.

RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion

IntroductionNearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. MethodsThis retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. ResultsFor 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). ConclusionsPatients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Panobinostat Induced Spatial In Situ Biomarkers Predictive of Anti-PD-1 Efficacy in Mouse Mammary Carcinoma.

Immunotherapies, including anti-PD-1 immune checkpoint blocking (ICB) antibodies, have revolutionized the treatment of many solid malignancies. However, their efficacy in breast cancer has been limited to a subset of patients with triple-negative breast cancer, where ICBs are routinely combined with a range of cytotoxic and targeted agents. Reliable biomarkers predictive of the therapeutic response to ICB in breast cancer are critically missing, though a combination response has been associated with immunogenic cell death (ICD). Here, we utilized a recently developed integrated analytical platform, the multiplex implantable microdevice assay (MIMA), to evaluate the presence and spatial cell relations of literature-based candidate markers predictive of ICB efficacy in luminal mouse mammary carcinoma. MIMA integrates (i) an implantable microdevice for the localized delivery of small amounts of drugs inside the tumor bed with (ii) sequential multiplex immunohistochemistry (mIHC) and spatial cell analysis pipelines to rapidly (within days) describe drug mechanisms of action and find predictive biomarkers in complex tumor tissue. We show that the expression of cleaved caspase-3, ICAM-1, neuropilin-1, myeloperoxidase, calreticulin, galectin-3, and PD-L1 were spatially associated with the efficacy of panobinostat, a pan-HDAC inhibitor that was previously shown to induce immunogenic cell death and synergize with anti-PD-1 in breast cancer. PD-L1 by itself, however, was not a reliable predictor. Instead, ICB efficacy was robustly identified through the in situ hotspot detection of galectin-3-positive non-proliferating tumor zones enriched in cell death and infiltrated by anti-tumor cytotoxic neutrophils positive for ICAM-1 and neuropilin-1. Such hotspots can be specifically detected using distance-based cluster analyses. Single-cell measurements of the functional states in the tumor microenvironment suggest that both qualitative and quantitative effects might drive effective therapy responses. Overall, the presented study provides (i) complementary biological knowledge about the earliest cell events of induced anti-tumor immunity in breast cancer, including the emergence of resistant cancer stem cells, and (ii) newly identified biomarkers in form of specific spatial cell associations. The approach used standard cell-type-, IHC-, and FFPE-based techniques, and therefore the identified spatial clustering of in situ biomarkers can be readily integrated into existing clinical or research workflows, including in luminal breast cancer. Since early drug responses were detected, the biomarkers could be especially applicable to window-of-opportunity clinical trials to rapidly discriminate between responding and resistant patients, thus limiting unnecessary treatment-associated toxicities.

Cell death-related biomarker SLC2A1 has a significant role in prognosis prediction and immunotherapy efficacy evaluation in pan-cancer.

Introduction: SLC2A1, a member of the SLC transporter family, is involved in a variety of cell death modalities and has been found to be associated with the prognosis and immune microenvironment of a variety of tumors. However, there is a lack of systematic and comprehensive studies on the role of SLC2A1 in pan-cancer. Methods: The mRNA, promoter methylation, and protein expression levels of SLC2A1 in pan-cancer were comprehensively evaluated using GEPIA2.0, TIMER2.0, and UALCAN databases. UCSCXenaShiny based on the cancer genomic atlas pan-cancer data and GEPIA2.0 database were used to assess the prognostic significance of SLC2A1 in pan-cancer. Genetic alterations in SLC2A1 were also evaluated using cBioPortal. The relevance of SLC2A1 to immune infiltrating cells in pan-cancer was evaluated using the XCELL algorithm in combination with the TIMER2.0 database. The correlation of SLC2A1 with the efficacy of immune checkpoint blocker (ICB) therapy was evaluated using the tumor immune dysfunction and exclusion (TIDE) score. The correlation of SLC2A1 with numerous immune-related markers was also evaluated using the TISIDB database. The correlation of SLC2A1 with tumor biological function was evaluated at the single-cell level using the CancerSEA database. Finally, the biological function of SLC2A1 was comprehensively evaluated using gene set enrichment analysis (GSEA) and protein interaction networks. Results: SLC2A1 expression is aberrant in a variety of tumors and is strongly associated with the prognosis of several cancers. SLC2A1 is significantly associated with a variety of immune infiltrating cells including CD8+ T cells, myeloid-derived suppressor cells and macrophages in a variety of tumors. Meanwhile, the expression of SLC2A1 significantly correlated with multiple immune-related markers. In addition, SLC2A1 can also predict the effect of immune checkpoint blocker therapy in some tumors. In a functional analysis, SLC2A1 was significantly associated with hypoxia, epithelial-mesenchymal transition, mTORC1 signaling, and multiple metabolic pathways in pan-cancer. Conclusion: Our study systematically and comprehensively summarizes the prognostic significance and immune-related role of SLC2A1 in pan-cancer and reveals the potential mechanism of SLC2A1 in regulating the tumor microenvironment and tumor behavior, providing a new effective pan-applicable biomarker for prognostic prediction and the evaluation of immunotherapeutic strategies for tumors.

PD-1/PD-L1 Immunotherapy: Combating Drug Resistance in Breast Cancer

In recent years, immune-checkpoint blocking therapy targeting the PD-1/PD-L1 axis has advanced tumor immunotherapy to a new level, with positive outcomes in a variety of malignant tumors. Tumors can avoid an antigen-specific T cell immune response by means of PD-1/PD-L1 signaling, which adversely controls T cell-mediated immune response. In clinical practice, it was shown that while some patients did have long-term success with immunotherapy, the majority eventually had resistance to drugs and recurrence. Hence, one of the main challenges that severely restricts the long-lasting benefits and widespread use of PD-1/PD-L1 blocking treatment is both primary and acquired resistance. Therefore, it is high time to understand the mechanisms of resistance for improving anti-PD-1/PD-L1 efficacy. In this review, we describe major signaling pathways that regulate PD-1/PD-L1 axis in cancers as well as the role of PD-1/PD-L1 in breast cancer development and progression. In addition, we further discuss the involvement of PD-1/PD-L1 axis in multi-drug resistance in cancers, which affected breast cancer and other solid tumor response rates and durability to treatment strategies.

Identification of a robust scoring system based on metabolic genes followed by in-depth validation of ATP1A3 in glioma

AimsIn the past few decades, the prognosis of glioma patients has not significantly improved. Therefore, to provide more precise medical services for glioma patients, it is urgent to identify more clinically meaningful subtypes, establish more robust clinical prediction models, and find more effective therapeutic targets. Materials and methodsFour distinct metabolic-associated subtypes were identified by the NMF algorithm based on metabolic genes (MEGs). A robust scoring system was constructed based on the differentially expressed genes (DEGs) screened from the four metabolic-associated subtypes with the LASSO regression algorithm and multivariate Cox regression analysis. Further analysis of scoring systems was done by different R packages. In addition, the ATP1A3 gene was screened and bioinformatics analysis of it was conducted on several public websites. GSEA software was utilized to search hallmark signaling pathways closely related to ATP1A3. Cytological experiments were used to investigate the role of ATP1A3 in the malignant progression of glioblastoma (GBM) cells. Key findingsFour metabolic-associated subtypes with significantly different clinicopathological characteristics were identified, and a robust scoring system with outstanding clinical application value was established. In addition, a tumor suppressor gene ATP1A3 was found, which is expected to be a potential therapeutic target for glioma. SignificanceThis study is of great significance in the diagnosis, prognosis, and prediction of the response to immune checkpoint blockers (ICBs) for glioma patients. More importantly, this study found a potential therapeutic target for glioma.

KLF5 inhibition potentiates anti-PD1 efficacy by enhancing CD8+ T-cell-dependent antitumor immunity.

Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods: We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8+ T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8+ T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions: Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.

Anti-PD1 does not improve pyroptosis induced by γδ T cells but promotes tumor regression in a pleural mesothelioma mouse model.

Mesothelioma is an aggressive tumor in the pleural cavity that is difficult to treat. Diagnosis is usually late with minimal treatment options available for the patients and with unfavorable outcomes. However, recent advances in immunotherapy using γδ T cells may have potential against mesothelioma, given its ample tumoricidal and tumor-migratory properties could allow its infiltration to the widespread tumor mass. Thus, we hypothesize that Vδ2 T cells can perform cytotoxic activities against mesothelioma especially when combined with immune checkpoint blocker against PD-1. Human Vδ2 T cells were expanded from peripheral blood mononuclear cells using Tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) plus IL-2 for 13 days, before used to test for cytotoxicity against mesothelioma cell lines. Mesothelioma-bearing mice was established by Intrapleural administration of mesothelioma cell lines to test for the efficacy of Vδ2 T cells plus anti-PD-1 antibody combination treatment. Pyroptosis was evaluated by cell morphology, western blot analysis, and ELISA experiments. Flow cytometry was used to examine expression of BTN2A1, BTN3A1, PD-L1, PD-L2 on mesothelioma cell lines. Immunofluorescence staining was performed to detect Vδ2 T cells post adoptive transfer and characteristics of pyroptosis in ex vivo mesothelioma tissue sections. Indeed, our data demonstrated that Vδ2 T cells killing mesothelioma can be enhanced by anti-PD-1 antibody in vitro, especially for high PD-1 expressing cells, and in vivo in the intrapleural mesothelioma mice model established by us. Adoptive transfer of Vδ2 T cells into these mice leads to tumor regression by 30-40% compared to control. Immunofluorescence of the tumor section confirmed infiltration of Vδ2 T cells into the tumor, especially to cells with BTN2A1 expression (a Vδ2 T cell activating molecule) despite PD-L1 co-localization. Interestingly, these cells co-expressed cleaved gasdermin D, suggesting that pyroptosis was induced by Vδ2 T cells. This was verified by Vδ2 T/mesothelioma co-culture experiments demonstrating membrane ballooning morphology, increased cleaved caspase-3 and gasdermin E, and upregulated IL-1β and IL-18. Vδ2 T cells plus anti-PD1 exhibited cytotoxicity against mesothelioma in vivo. However, we found no advantage for anti-PD-1 against PD-1 high expressing Vδ2 T cells in promoting pyroptosis. Taken together, our work demonstrated that Vδ2 T cells combined with anti-PD-1 antibody can be developed as a potential combination immunotherapy for mesothelioma.

Identification and development of TP53 mutation-associated Long non-coding RNAs signature for optimized prognosis assessment and treatment selection in hepatocellular carcinoma.

The TP53 gene is estimated to be mutated in over 50% of tumors, with the majority of tumors exhibiting abnormal TP53 signaling pathways. However, the exploration of TP53 mutation-related LncRNAs in Hepatocellular carcinoma (HCC) remains incomplete. This study aims to identify such LncRNAs and enhance the prognostic accuracy for Hepatoma patients. Differential gene expression was identified using the "limma" package in R. Prognosis-related LncRNAs were identified via univariate Cox regression analysis, while a prognostic model was crafted using multivariate Cox regression analysis. Survival analysis was conducted using Kaplan-Meier curves. The precision of the prognostic model was assessed through ROC analysis. Subsequently, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm were executed on the TCGA dataset via the TIDE database. Fractions of 24 types of immune cell infiltration were obtained from NCI Cancer Research Data Commons using deconvolution techniques. The protein expression levels encoded by specific genes were obtained through the TPCA database. In this research, we have identified 85 LncRNAs associated with TP53 mutations and developed a corresponding signature referred to as TP53MLncSig. Kaplan-Meier analysis revealed a lower 3-year survival rate in high-risk patients (46.9%) compared to low-risk patients (74.2%). The accuracy of the prognostic TP53MLncSig was further evaluated by calculating the area under the ROC curve. The analysis yielded a 5-year ROC score of 0.793, confirming its effectiveness. Furthermore, a higher score for TP53MLncSig was found to be associated with an increased response rate to immune checkpoint blocker (ICB) therapy (p = .005). Patients possessing high-risk classification exhibited lower levels of P53 protein expression and higher levels of genomic instability. The present study aimed to identify and validate LncRNAs associated with TP53 mutations. We constructed a prognostic model that can predict chemosensitivity and response to ICB therapy in HCC patients. This novel approach sheds light on the role of LncRNAs in TP53 mutation and provides valuable resources for analyzing patient prognosis and treatment selection.

Self-driven immune checkpoint blockade and spatiotemporal-sensitive immune response monitoring in acute myeloid leukemia using an all-in-one turn-on bionanoprobe.

Immune checkpoint (ICP) blockade (ICB) is one of the most promising immunotherapies for acute myeloid leukemia (AML). However, owing to their heterogeneity, AML cells may cause uncoordinated metabolic fluxes and heterogeneous immune responses, inducing the release of a spatiotemporally sensitive immune response marker. Timely and in situ detection of immune responses in ICB therapy is important for therapeutic strategy adjustment. Herein, we constructed an all-in-one nanoprobe for self-driving ICB and simultaneously detecting an immune response in the same AML cell in vivo, thus enabling accurate evaluation of heterogenetic immune responses in living AML mice without additional drug treatment or probe processes. The nature-inspire polydopamine (PDA) nanoparticles loaded with an ICP blocker were targeted to the leukocyte immunoglobulin like receptor B4 (a new ICP) of AML cells to induce the release of immune response marker granzyme B (GrB). The PDA nanoparticles were additionally paired with carbon-derived graphene quantum dots (GQDs) to construct a full-organic 'turn-on' bionanoprobe that can transfer fluorescence resonance energy for GrB detection. This multifunctional nanoprobe was validated for triggering ICB therapy and monitoring the changes of GrB levels in real-time both in vitro and in vivo. The organic nanoprobe showed excellent permeability and retention in tumor cells and high biocompatibility in vivo. This bionanoprobe orderly interacted with the upstream ICP molecules and downstream signal molecule GrB, thereby achieving in situ immune response signals within the therapeutic efficacy evaluation window.

Overcoming Malignant Glioma Therapeutic Challenges: Nanocarrier-Mediated Delivery of Immune Checkpoint Blockers via Nasal Route

Malignant glioma represents a prevailing malignancy within both paediatric and adult populations, necessitating advanced therapeutic interventions. Traditional therapeutic avenues encompassing surgical resection, radiotherapy, and chemotherapy have yielded unsatisfactory clinical outcomes

Retracted: Value of a Signature of Immune-Related Genes in Predicting the Prognosis of Melanoma and Its Responses to Immune Checkpoint Blocker Therapies.

[This retracts the article DOI: 10.1155/2022/9633416.].

Oncogene-addicted solid tumors and microbiome-lung cancer as a main character: a narrative review.

Lung cancer stands as the main cause of cancer-related deaths worldwide. With the advent of immunotherapy and the discovery of targetable oncogenic driver genes, although prognosis has changed in the last few years, survival rates remain dismal for most patients. This emphasizes the urgent need for new strategies that could enhance treatment in precision medicine. The role of the microbiota in carcinogenesis constitutes an evolving landscape of which little is known. It has been suggested these microorganisms may influence in responses, resistance, and adverse effects to cancer treatments, particularly to immune checkpoint blockers. However, evidence on the impact of microbiota composition in oncogene-addicted tumors is lacking. This review aims to provide an overview of the relationship between microbiota, daily habits, the immune system, and oncogene-addicted tumors, focusing on lung cancer. A PubMed and Google Scholar search from 2013 to 2024 was conducted. Relevant articles were reviewed in order to guide our research and generate hypothesis of clinical applicability. Microbiota is recognized to participate in immune reprogramming, fostering inflammatory, immunosuppressive, or anti-tumor responses. Therefore, identifying the microbiota that impact response to treatment and modulating its composition by interventions such as dietary modifications, probiotics or antibiotics, could potentially yield better outcomes for cancer patients. Additionally, targeted therapies that modulate molecular signaling pathways may impact both immunity and microbiota. Understanding this intricate interplay could unveil new therapeutic strategies. By comprehending how microbiota may influence efficacy of targeted therapies, even though current evidence is scarce, we may generate interesting hypotheses that could improve clinical practice.

Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade.

The binding of programmed death-1 (PD-1) on the surface of T cells and PD-1 ligand 1 (PD-L1) on tumor cells can prevent the immune-killing effect of T cells on tumor cells and promote the immune escape of tumor cells. Therefore, immune checkpoint blockade targeting PD-1/PD-L1 is a reliable tumor therapy with remarkable efficacy. However, the main challenges of this therapy are low response rate and acquired resistance, so that the outcomes of this therapy are usually unsatisfactory. This review begins with the description of biological structure of the PD-1/PD-L1 immune checkpoint and its role in a variety of cells. Subsequently, the therapeutic effects of immune checkpoint blockers (PD-1 / PD-L1 inhibitors) in various tumors were introduced and analyzed, and the reasons affecting the function of PD-1/PD-L1 were systematically analyzed. Then, we focused on analyzing, sorting out and introducing the possible underlying mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade including abnormal expression of PD-1/PD-L1 and some factors, immune-related pathways, tumor immune microenvironment, and T cell dysfunction and others. Finally, promising therapeutic strategies to sensitize the resistant patients with PD-1/PD-L1 blockade treatment were described. This review is aimed at providing guidance for the treatment of various tumors, and highlighting the drug resistance mechanisms to offer directions for future tumor treatment and improvement of patient prognosis.

Manipulation of PD-L1 Endosomal Trafficking Promotes Anticancer Immunity.

The aberrant regulation of PD-L1 in tumor cells remains poorly understood. Here, the authorssystematically investigate the endosomal trafficking of plasma membrane PD-L1 in tumor cells.They show that plasma membrane PD-L1 is continuously internalized, and then trafficked from early endosomes to multivesicular bodies/late endosomes, recycling endosomes, lysosomes, and/or extracellular vesicles (EVs). This constitutive endocytic trafficking of PD-L1 is Rab5- and clathrin-dependent. Triazine compound 6J1 blocks the endosomal trafficking of PD-L1 and induces its accumulation in endocytic vesicles by activating Rab5. 6J1 also promotes exosomal PD-L1 secretion by activating Rab27. Together, these effects result in a decrease in the membrane level of PD-L1 in 6J1-treated tumor cells and enables tumor cells to be more susceptible to the tumor-killing activity of T cells in vitro. 6J1 also increases tumor-infiltrating cytotoxic T cells and promotes chemokines secretion in the tumor microenvironment. Rab27 knockdown abolishes 6J1-induced PD-L1 secretion in EVs and revokes the exhausted tumor-infiltrating T cells in tumors, thereby improving the anticancer efficacy of 6J1. Furthermore, a combination of 6J1 and an anti-PD-1 antibody significantly improves the anticancer immune response. Therefore, manipulating PD-L1 endosomal trafficking provides a promising means to promote an anticancer immune response in addition to the immune checkpoint-blocking antibody therapy.

Foods may modify responsiveness to cancer immune checkpoint blockers by altering both the gut microbiota and activation of estrogen receptors in immune cells

Estrogen receptor alpha positive (ERα+) breast cancers are refractory to immune checkpoint blocker (ICB) monotherapy, while ICBs are part of a standard of care for triple negative breast cancers (TNBCs). Besides tumor ERα expression, another difference between the two types of breast cancers is that only ERα+ patients exhibit elevated tumor estradiol (E2) levels, compared with surrounding normal tissue. Recent evidence suggests that inhibition of ERα or activation of ERβ or G protein-coupled estrogen receptor (GPER) in immune cells in the tumor microenvironment (TME) increases tumor CD8+ T cell infiltration and boosts cancer ICB response. Ovarian and adipose-produced estrogens activate all three ERs equally, but plant estrogens (phytochemicals) preferentially activate ERβ or GPER. The gut microbiota is a key player in determining response to ICBs, and high abundance of Firmicutes and high fecal levels of short chain fatty acids (SCFAs) that are mainly produced by Firmicutes, are linked to improved effectiveness of ICB therapy. Interestingly, the gut microbiota of ERα+ breast cancer patients contain significantly lower abundance of Firmicutes species than the gut microbiota of TNBC patients. Many factors modify the gut microbiota, especially diet. The gut microbiota altering diets include (i) foods high in ERβ and GPER activating plant phytochemicals or (ii) SCFAs producing fiber that also reduces circulating estrogen levels, (iii) estrogen levels reducing fasting/caloric restriction, or (iv) ketogenic diet which reduces fecal SCFA levels but increases hepatic production of SCFA receptor activating ketone bodies. It is thus possible that certain foods or dietary patterns can modify both the gut microbiota and activation of the estrogen receptors in the tumor immune cells, and consequently regulate the effectiveness of ICB therapy against cancers.

Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis

BackgroundFor patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. MethodsWe performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. ResultsSix phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3–26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6–34.6) and 66.9% (95% CI: 59.6–75.2%), respectively. The incidence of grade 3–5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. ConclusionsDespite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.

Immune Checkpoint and Other Receptor-Ligand Pairs Modulating Macrophages in Cancer: Present and Prospects

Immunotherapy, especially immune checkpoint blocking, has become the primary anti-tumor treatment in recent years. However, the current immune checkpoint inhibitor (ICI) therapy is far from satisfactory. Macrophages are a key component of anti-tumor immunity as they are a common immune cell subset in tumor tissues and act as a link between innate and adaptive immunity. Hence, understanding the regulation of macrophage activation in tumor tissues by receptor-ligand interaction will provide promising macrophage-targeting strategies to complement current adaptive immunity-based immunotherapy and traditional anti-tumor treatment. This review aims to offer a systematic summary of the current advances in number, structure, expression, biological function, and interplay of immune checkpoint and other receptor-ligand between macrophages and tumor cells.

Combined immunotherapy for metastatic triple-negative breast cancer based on PD-1/PD-L1 immune checkpoint blocking.

Metastatic triple negative breast cancer is not only the worst prognosis and the strongest invasive subtype of breast cancer, but also the most immunogenic subtype, so it can be reasonably predicted that immunotherapy can play a positive role in the treatment of metastatic triple negative breast cancer. However, the effect of using PD-1/PD-L1 immune checkpoint inhibitors alone is not very ideal. In recent years, the regimen of combined therapy has been emerging. This article reviews the application of combined immunotherapy based on PD-1/PD-L1 inhibitors in metastatic triple negative breast cancer, including chemotherapy, targeted therapy, radiotherapy and oncolytic virus therapy. The problems existing in combined therapy and the possibility of future research are discussed, which can provide a reference for the selection of treatment options for patients with metastatic triple negative breast cancer in different situations.

Molecular subtypes and a prognostic model for hepatocellular carcinoma based on immune- and immunogenic cell death-related lncRNAs.

Accumulating evidence shows that immunogenic cell death (ICD) enhances immunotherapy effectiveness. In this study, we aimed to develop a prognostic model combining ICD, immunity, and long non-coding RNA biomarkers for predicting hepatocellular carcinoma (HCC) outcomes. Immune- and immunogenic cell death-related lncRNAs (IICDLs) were identified from The Cancer Genome Atlas and Ensembl databases. IICDLs were extracted based on the results of differential expression and univariate Cox analyses and used to generate molecular subtypes using ConsensusClusterPlus. We created a prognostic signature based on IICDLs and a nomogram based on risk scores. Clinical characteristics, immune landscapes, immune checkpoint blocking (ICB) responses, stemness, and chemotherapy responses were also analyzed for different molecular subtypes and risk groups. A total of 81 IICDLs were identified, 20 of which were significantly associated with overall survival (OS) in patients with HCC. Cluster analysis divided patients with HCC into two distinct molecular subtypes (C1 and C2), with patients in C1 having a shorter survival time than those in C2. Four IICDLs (TMEM220-AS1, LINC02362, LINC01554, and LINC02499) were selected to develop a prognostic model that was an independent prognostic factor of HCC outcomes. C1 and the high-risk group had worse OS (hazard ratio > 1.5, p < 0.01), higher T stage (p < 0.05), higher clinical stage (p < 0.05), higher pathological grade (p < 0.05), low immune cell infiltration (CD4+ T cells, B cells, macrophages, neutrophils, and myeloid dendritic cells), low immune checkpoint gene expression, poor response to ICB therapy, and high stemness. Different molecular subtypes and risk groups showed significantly different responses to several chemotherapy drugs, such as doxorubicin (p < 0.001), 5-fluorouracil (p < 0.001), gemcitabine (p < 0.001), and sorafenib (p < 0.01). Our study identified molecular subtypes and a prognostic signature based on IICDLs that could help predict the clinical prognosis and treatment response in patients with HCC.