Immunological Therapy Research Articles

BTKi combined with chemical immunotherapy in the initial treatment of aggressive mantle cell lymphoma: A retrospective study.

To explore the safety and efficacy of Bruton's tyrosine kinase inhibitor (BTKi) combined with immunological therapy in untreated patients with aggressive mantle cell lymphoma. A retrospective study was conducted on 9 previously untreated patients who received BTKi combined with immunological therapy, which means using immunological therapy and BTKi at the same time. The median age of the patients was 61 years, 7 were males, and the median follow-up time was 14 months. Among the 7 evaluable patients, the median follow-up was 14 months, and the objective remission rate was 100% (complete remission rate 86%, partial remission rate 14%), while the median progression-free survival and overall survival were not achieved. No patients were dead. The progression-free survival rate of 6 patients in the low-risk group was 100%. The combination of BTKi and chemoimmunotherapy has shown excellent therapeutic results in untreated patients of aggressive mantle cell lymphoma. At the same time, it also can prolong the survival time of high-risk patients. The combined therapy has acceptable safety in previously untreated patients. Hematological toxicity is the most common side effect and infection is the second one. A rash reaction was seen occasionally. There are no heart-related adverse events in the study. There are no new adverse effects caused by the combined treatment.

A case of posttransplant isolated extramedullary relapse of acute lymphoblastic leukemia achieving durable treatment-free remission with blinatumomab and donor lymphocyte infusion.

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance.

CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies.

Combination therapy of anti-programmed cell death protein-1 (PD-1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single-cell RNA sequencing (scRNA-seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA-seq) on CCL5-stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor-bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC.

From foes to friends: rethinking the role of lymph nodes in prostate cancer.

Clinically localized prostate cancer is often treated with radical prostatectomy combined with pelvic lymph node dissection. Data suggest that lymph node dissection does improve disease staging, but its therapeutic value has often been debated, with few studies showing that lymph node removal directly improves oncological outcomes; however, lymph nodes are an important first site of antigen recognition and immune system activation and the success of many currently used immunological therapies hinges on this dogma. Evidence, particularly in the preclinical setting, has demonstrated that the success of immune checkpoint inhibitors is dampened by the removal of tumour-draining lymph nodes. Thus, whether lymph nodes are truly 'foes' or whether they are actually 'friends' in oncological care is an important idea to discuss.

Cardiovascular toxicities of immune therapies for cancer-a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Advances in hepatocellular carcinoma drug resistance models.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Surgery has been the major treatment method for HCC owing to HCC's poor sensitivity to radiotherapy and chemotherapy. However, its effectiveness is limited by postoperative tumour recurrence and metastasis. Systemic therapy is applied to eliminate postoperative residual tumour cells and improve the survival of patients with advanced HCC. Recently, the emergence of various novel targeted and immunotherapeutic drugs has significantly improved the prognosis of advanced HCC. However, targeted and immunological therapies may not always produce complete and long-lasting anti-tumour responses because of tumour heterogeneity and drug resistance. Traditional and patient-derived cell lines or animal models are used to investigate the drug resistance mechanisms of HCC and identify drugs that could reverse the resistance. This study comprehensively reviewed the established methods and applications of in-vivo and in-vitro HCC drug resistance models to further understand the resistance mechanisms in HCC treatment and provide a model basis for possible individualised therapy.

Gut microbiome, and immune cells mediated effect on depression: A two-step, two-sample Mendelian randomization analysis

BackgroundThe gut microbiota (GM) plays an important role in the development of immune-related diseases, and the immune response is one of the pathomechanisms of depression (Dep); whether the effect of GM on Dep is mediated by immune cells (ImC) is unclear. ObjectiveImC may mediate the effect of GM on Dep. Our aim is to identify and quantify the role of immune characteristics as potential mediators. MethodsPooled statistics for GM (n = 7738) and ImC (n = 3757) were obtained from publicly available genome-wide association studies (GWAS), and for Dep (n = 47,696) from the Finnish database R10. We used a mediated Mendelian randomization (MR) study to investigate the causal relationship between GM and Dep and the mediating role of ImC between GM and Dep associations. ResultsThe results showed that the genetically predicted GM was significantly correlated with both ImC as well as Dep. MR analysis identified five microbiomes that had significant causal effects on Dep (Methionine biosynthesis III, PWY-6737-Starch degradation V, Parasutterella excrementihominis, Parasutterella, and Lysine biosynthesis I). In addition, five of the 26 ImC trait significantly associated with GM were most closely associated with Dep (T cell %lymphocyte、CD28-CD127-CD25++CD8br AC、CD28-CD8br AC、CD27 receptor on peripheral blood plasma cells (CD27 on PB/PC) and CD11b receptor on mononuclear myeloid-derived suppressor cells (CD11b on Mo MDSC)). This mediated MR illustrates the causal role of methionine biosynthesis III on Dep (IVW: OR = 1.08, 95%CI [1.04,1.14], P = 0.001). And there was no strong evidence for a causal effect of depression on methionine biosynthesis III. In the B cell group, the proportion of CD27 on PB/PC mediated was 7.88 %(95%CI [−0.04,0.03]) of the total effect. This study further suggests that Dep patients should actively seek immunologic intervention therapy. ConclusionThis MR study found that GM may play a causal role in Dep by mediating ImC. Our findings will help to understand the pathogenic mechanism of GM in Dep and the risk of immune mediation.

Labeling of Bruton's Tyrosine Kinase (BTK) Inhibitor [11C]BIO-2008846 in Three Different Positions and Measurement in NHP Using PET.

Bruton's tyrosine kinase (BTK) is pivotal in B-cell signaling and a target for potential anti-cancer and immunological disorder therapies. Improved selective reversible BTK inhibitors are in demand due to the absence of direct BTK engagement measurement tools. Promisingly, PET imaging can non-invasively evaluate BTK expression. In this study, radiolabeled BIO-2008846 ([11C]BIO-2008846-A), a BTK inhibitor, was used for PET imaging in NHPs to track brain biodistribution. Radiolabeling BIO-2008846 with carbon-11, alongside four PET scans on two NHPs each, showed a homogeneous distribution of [11C]BIO-2008846-A in NHP brains. Brain uptake ranged from 1.8% ID at baseline to a maximum of 3.2% post-pretreatment. The study found no significant decrease in regional VT values post-dose, implying minimal specific binding of [11C]BIO-2008846-A compared to free and non-specific components in the brain. Radiometabolite analysis revealed polar metabolites with 10% unchanged radioligand after 30 min. The research highlighted strong brain uptake despite minor distribution variability, confirming passive diffusion kinetics dominated by free and non-specific binding.

P-405 Effects of intrauterine perfusion of autologous platelet-rich plasma on recurrent implantation failure in frozen-thawed embryo transfer: a meta-analysis of randomized controlled trials

Abstract Study question We aimed to evaluate the effect of the platelet-rich plasma （PRP) on pregnancy outcomes in patients with RIF undergoing frozen-thawed embryo transfer (FET). Summary answer Intrauterine infusion of PRP might have more beneficial effects on pregnancy outcomes in RIF patients undergoing FET. What is known already Immunological therapies are of great interest to specialists in reproductive medicine. The immune therapies use intrauterine infusion (i.e., PRP, PBMC, G-CSF, and hCG) for endometrial immunomodulation. Despite the limited number of publications available, the results are encouraging. In the network meta-analysis, PRP, PBMC, C-GCSF, and hCG administration all significantly increased embryo implantation and clinical pregnancy compared to controls. Additionally, PRP administration resulted in a higher live birth rate than the control. This year, more research has focused on PRP as an innovative method to treat RIF. Study design, size, duration Medline, Embase, and Cochrane Controlled Register of Trials (CENTRAL) were searched from inception to July 29, 2023. The randomized controlled trials (RCTs) reporting on pregnancy outcomes of women with RIF who were administered PRP undergoing FET were included. We conducted a meta-analysis where possible using a fixed effects model. The Cochrane Handbook was used to assess the risk of bias for RCTs. Binary outcomes were pooled using risk ratio (RR) with 95% confidence intervals (CIs). Participants/materials, setting, methods Seven RCTs were included with 1,014 RIF women. The final number of women analyzed was 508 with intrauterine infusion PRP and 506 without it. Main results and the role of chance Meta-analysis showed that compared to the controls, the women who received PRP had a significantly higher embryo implantation rate (n = 2, risk ratio (RR) 2.34, 95% CI 1.65 to 3.32; P < 0.00001, I2 = 0%), biochemical pregnancy rate (n = 5, RR 1.94, 95% CI 1.60 to 2.36; P < 0.00001, I2 = 0%), clinical pregnancy rate (n = 7, RR 2.31, 95% CI 1.89 to 2.82; P < 0.00001, I2 = 0%), ongoing pregnancy rate (n = 3, RR 2.70, 95% CI 1.79 to 4.05, P = 0.0004, I2 = 31%), and multiple pregnancy rate (n = 3, RR 2.67, 95% CI 1.07 to 6.68, P = 0.04, I2 = 0%). However, PRP was not attributable to reduce the miscarriage rate (n = 3, RR 1.15, 95% CI 0.40 to 3.35; P = 0.80, I2 = 0%). Limitations, reasons for caution The proportion of small-sample studies included has to some extent affected the validity of the results. There were some variations regarding the PRP preparation process, which may result in a variable composition and concentrations of its different contents. Wider implications of the findings Intrauterine infusion PRP in patients with RIF who underwent FET may improve the pregnancy outcomes assessed in RCTs, including clinical pregnancy and ongoing pregnancy. Therefore, we suggest that PRP be included in endometrial preparation protocols. Trial registration number not applicable

The prognostic role of albumin levels in lung cancer patients receiving third-line or advanced immunotherapy: a retrospective study.

Immunotherapy functions by leveraging immunoregulation drugs to bolster the immune system's capacity to identify and eliminate cancerous cells. In contrast to radiotherapy and chemotherapy, immunotherapy exhibits diminished side effects, heightened efficacy, and prolonged survival rates. Nevertheless, meticulous exploration into the determinants governing the advantageous effects of immunotherapy among patients who have previously undergone multiple prior therapies has yet to be conducted. Albumin (ALB) as a nutritional indicator has not been thoroughly studied for its prognostic effect on efficacy or survival. This study aims to identify factors that influence treatment outcomes among patients undergoing third-line or later immunological therapies. A cohort of 250 lung cancer patients undergoing toripalimab or tislelizumab immunotherapy was the focal point of data collection. The determination of the median value facilitated the establishment of a cut-off point, enabling the categorization of continuous variables. After data collection, a series of statistical analyses of various clinical factors at baseline were performed, including nonparametric tests, logistic regression, and Cox proportional risk modeling. The last follow-up was in May 2022. The primary study endpoint was overall survival (OS). A total of 250 patients were enrolled in the study, of which 129 patients received first- or second-line immunotherapy and 121 patients received third-line or subsequent immunotherapy. According to Cox multifactor regression analysis, in patients receiving either first- or second-line therapy, the ALB level exhibited negligible prognostic relevance (P>0.05). However, in patients subjected to immunotherapy beyond the second line, the ALB level manifested significant prognostic importance (P=0.039). Notably, patients demonstrating elevated ALB levels achieved a higher disease control rate (DCR) (70.0% vs. 52.5%, P=0.05) and displayed a tendency towards a heightened objective response rate (ORR) (20.0% vs. 16.4%, P=0.61) in comparison to those with lower ALB levels. Among patients undergoing immunotherapy in the third line or subsequent treatment phases, elevated ALB levels in baseline correlated with DCR and OS. Thus, the pre-immunotherapy ALB level emerges as an autonomous predictor of OS in patients subjected to third- or later line immunotherapy interventions.

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators.

In oral squamous cell carcinoma (OSCC) tissues, an immunotolerant situation triggered by immune checkpoints (ICPs) can be observed. Immune checkpoint inhibitors (ICIs) against the PD1/PD-L axis are used with impressive success. However, the response rate is low and the development of acquired resistance to ICI treatment can be observed. Therefore, new treatment strategies especially involving immunological combination therapies need to be developed. The novel negative immune checkpoint BTLA has been suggested as a potential biomarker and target for antibody-based immunotherapy. Moreover, improved response rates could be displayed for tumor patients when antibodies directed against BTLA were used in combination with anti-PD1/PD-L1 therapies. The aim of the study was to check whether the immune checkpoint BTLA is overexpressed in OSCC tissues compared to healthy oral mucosa (NOM) and could be a potential diagnostic biomarker and immunological target in OSCC. In addition, correlation analyses with the expression of other checkpoints should clarify more precisely whether combination therapies are potentially useful for the treatment of OSCC. A total of 207 tissue samples divided into 2 groups were included in the study. The test group comprised 102 tissue samples of OSCC. Oral mucosal tissue from 105 healthy volunteers (NOM) served as the control group. The expression of two isoforms of BTLA (BTLA-1/2), as well as PD1, PD-L1/2 and CD96 was analyzed by RT-qPCR. Additionally, BTLA and CD96 proteins were detected by IHC. Expression levels were compared between the two groups, the relative differences were calculated, and statistical relevance was determined. Furthermore, the expression rates of the immune checkpoints were correlated to each other. BTLA expression was significantly increased in OSCC compared to NOM (pBTLA_1 = 0.003; pBTLA_2 = 0.0001, pIHC = 0.003). The expression of PD1, its ligands PD-L1 and PD-L2, as well as CD96, were also significantly increased in OSCC (p ≤ 0.001). There was a strong positive correlation between BTLA expression and that of the other checkpoints (p < 0.001; ρ ≥ 0.5). BTLA is overexpressed in OSCC and appears to be a relevant local immune checkpoint in OSCC. Thus, antibodies directed against BTLA could be potential candidates for immunotherapies, especially in combination with ICI against the PD1/PD-L axis and CD96.

Incidencia de micosis fungoide en pacientes con psoriasis vulgar crónica

Background: Psoriasis is a chronic dermatosis, characterized by erythematous and scaly plaques, affecting 2 -3% of people worldwide. And on the other hand we have mycosis fungoides, the most common cutaneous T-cell lymphoma, which presents manifestations that vary from erythematous macules to tumors. These two pathologies are independent, however, their clinical and pathological similarity has generated erroneous diagnoses. However, literature has marked a possible connection between the two. The relationship between psoriasis and mycosis fungoides, as well as the appearance of mycosis fungoides after systemic treatment for psoriasis, has generated a great enigma and really requires exhaustive study. Material and methods: A systematic review of publications of studies on the incidence of mycosis fungoides in chronic psoriasis vulgaris patients is carried out, and a meta-analysis will be carried out that incorporates all the published information available using the online databases pubmed, google scholar, trip medical database, Embase, prospero International prospective register of systematic reviews Results: The systematic review concluded that 47 cases met the inclusion criteria, that is, patients with a history of long-standing psoriasis vulgaris, of which 38 patients received biological therapy and 32 patients developed mycosis fungoides. Conclusion: The association between mycosis fungoides and long-standing psoriasis vulgaris is a complex issue, mainly due to its difficulty in clinically differentiating both diseases, which often generates an erroneous diagnosis. Likewise, there have been cases of coexistence of both pathologies and the appearance of mycosis fungoides secondary to long-standing treatments for psoriasis vulgaris. A clear association between psoriasis and mycosis fungoides has not yet been established. However, it is possible that this connection is favored by the immunopathology of psoriasis due to the constant activation of the immune system and the presence of Th17 cells, predisposing to the development of mycosis fungoides. However, there are few studies on these topics specifically. It is imperative that more studies be conducted to understand the mechanisms involved, develop and establish more specific management guidelines against therapies for patients with pre-existing risk factors. Some studies have suggested an association between the use of biologic therapies for psoriasis and an increased risk of developing or exacerbating mycosis fungoides in certain patients. However, the evidence is still inconclusive and more research is needed to fully understand this relationship. Concern about the impact of immunological therapies in long-standing psoriasis vulgaris highlights the need for constant monitoring and long-term investigations to better understand the long-term effects of these treatments. The actual incidence and prevalence of the relationship between long-standing psoriasis vulgaris and mycosis fungoides cannot be determined with certainty

Neuro-oncologic Emergencies.

Neuro-oncologic emergencies have become more frequent as cancer remains one of the leading causes of death in the United States, second only to heart disease. This article highlights key aspects of epidemiology, diagnosis, and management of acute neurologic complications in primary central nervous system malignancies and systemic cancer, following three thematic classifications: (1) complications that are anatomically or intrinsically tumor-related, (2) complications that are tumor-mediated, and (3) complications that are treatment-related. The main driver of mortality in patients with brain metastasis is systemic disease progression; however, intracranial hypertension, treatment-resistant seizures, and overall decline due to increased intracranial burden of disease are the main factors underlying neurologic-related deaths. Advances in the understanding of tumor-specific characteristics can better inform risk stratification of neurologic complications. Following standardized grading and management algorithms for neurotoxic syndromes related to newer immunologic therapies is paramount to achieving favorable outcomes. Neuro-oncologic emergencies span the boundaries of subspecialties in neurology and require a broad understanding of neuroimmunology, neuronal hyperexcitability, CSF flow dynamics, intracranial compliance, and neuroanatomy.

Hyper IgE syndrom suspect - Case Report

Introduction: Hyper IgE syndrome (HIES) is a rare condition of the immune system characterized by various types of infections throughout life. This syndrome can be divided into two types, dominant heterozygous related to STAT3 gene mutation and recessive homozygous, which can also be subdivided into two groups related to Tyk2 and DOCK8 gene mutations, each presenting variations in their clinical presentations. Diagnosis is based on genetic sequencing, although there are some symptoms, clinical factors, and hereditary factors that can assist in diagnosis. There is no specific treatment for this pathology, with the main focus being on controlling infections and infusing immunological therapies such as intravenous immunoglobulin G.

Tisagenlecleucel for Treatment of Refractory or Relapsed B-cell Acute Lymphoblastic Leukemia (R/R B-All): A Systematic Review of Cost-Effectiveness Analysis

Tisagenlecleucel is a new immunological therapy in refractory or relapsed B-cell lymphoblastic leukemia with high expense. Objective: To assess the quality as well as analyze characteristics and results of cost-effectiveness analysis (CEA) of tisagenlecleucel immunological therapy in children with R/R B-ALL. Method: To analyze systematic review of articles published during the period of 2017-2023 in Pubmed, ScienceDirect, GoogleScholar, Cochrane databases. Result: 10 selected studies were carried out in 8 nations with different cost units and discount rates. Compared therapies were standard therapy of each country included Blinatumomab, Clo-C, Clo-M, FLA-IDA, FLAG-IDA. Of 10 studies, 70% was considered cost-effectiveness, 20% non-conclusion and only 10% not cost-effectiveness. Conclusion: Tisagenlecleucel’s cost is the highest among compared therapies but it can be cost-effective in a nation with WTP threshold of $100.000-$150.000.&#x0D; Keywords: Systematic review, cost-effective, tisagenlecleucel, CAR-T, acute lymphoblastic leukemia.&#x0D; &#x0D;

Current issues in dose-finding designs: A response to the US Food and Drug Adminstration's Oncology Center of Excellence Project Optimus.

With the advent of targeted agents and immunological therapies, the medical research community has become increasingly aware that conventional methods for determining the best dose or schedule of a new agent are inadequate. It has been well established that conventional phase I designs cannot reliably identify safe and effective doses. This problem applies, generally, for cytotoxic agents, radiation therapy, targeted agents, and immunotherapies. To address this, the US Food and Drug Administration's Oncology Center of Excellence initiated Project Optimus, with the goal "to reform the dose optimization and dose selection paradigm in oncology drug development." As a response to Project Optimus, the articles in this special issue of Clinical Trials review recent advances in methods for choosing the dose or schedule of a new agent with an overall objective of informing clinical trialists of these innovative designs. This introductory article briefly reviews problems with conventional methods, the regulatory changes that encourage better dose optimization designs, and provides brief summaries of the articles that follow in this special issue.

A commentary on 'The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in the targeted therapy and immunological therapy era: a systematic review and meta-analysis' [Int J Surg (2023) 109:982-994

A commentary on 'The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in the targeted therapy and immunological therapy era: a systematic review and meta-analysis' [Int J Surg (2023) 109:982-994

The engineered exosomes targeting ferroptosis: A novel approach to reverse immune checkpoint inhibitors resistance.

Immune checkpoint inhibitors (ICIs) have been extensively used in immunological therapy primarily due to their ability to prolong patient survival. Although ICIs have achieved success in cancer treatment, the resistance of ICIs should not be overlooked. Ferroptosis is a newly found cell death mode characterized by the accumulation of reactive oxygen species (ROS), glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, which has been demonstrated to be beneficial to immunotherapy and combining ferroptosis and ICIs to exploit new immunotherapies may reverse ICIs resistance. Exosomes act as mediators in cell-to-cell communication that may regulate ferroptosis to influence immunotherapy through the secretion of biological molecules. Thus, utilizing exosomes to target ferroptosis has opened up exciting possibilities for reversing ICIs resistance. In this review, we summarize the mechanisms of ferroptosis improving ICIs therapy and how exosomes regulate ferroptosis through adjusting iron metabolism, blocking the ROS accumulation, controlling ferroptosis defense systems, and influencing classic signaling pathways and how engineered exosomes target ferroptosis and improve ICIs efficiency.

Abstract 5172: miRNA lncRNA network associated with response to cemiplimab in cutaneous squamous cell carcinoma

Abstract Introduction: For advanced cSCC the use of immunological therapies relies on the biology of the tumor, characterized by high mutational burden. However, although the anti-PD1 cemiplimab showed to be a promising treatment option, future research focusing on the use of biomarkers to predict treatment response are needed. Since increasing number of studies has revealed the crucial roles of non-coding RNAs, such as miRNAs and lncRNAs in the development of SCC, the present study had the purpose to explore the lncRNA-miRNA-mRNA networks associated with response to anti-PD1. For this purpose the experimental procedure envisaged a preliminary in silico analysis followed by the investigation of identified miRNA and lncDNA in liquid biopsy. Methods: For the in silico study, GSE139505 RNA-sequencing raw data have been retrieved from SRA, including 7 Healthy Samples and 9 cSCC biopsies. Two matrices have been prepared, including coding genes and lncRNAs. Normalized coding gene matrix have been used as input to perform GSEA. Coexpression analysis between lncRNAs and Core enrichment genes resulting from GSEA was performed. Biological network including validated miRNA-gene interactions (TarBase) and lncRNA-miRNA interactions (lncBase) has been built-up through Cytoscape. MCODE analysis to identify subnetwork with the closest relationships was performed. The quantification of identified miRNAs (miR-125a, miR-125b, miR-148a, miR-148b) and lnc (AF131217.1, RP11-362F19.1, PVT1, LINC00665) was performed in pre-therapy plasma samples of 34 cSCC patients, categorized according to clinical response to cemiplimab, in responders and non-responders. miRNA-specific RT primers were used for reverse transcription by ddPCR. Results: The computational analysis revealed a significant enrichment of two gene sets related to immunotherapy, namely the Reactome_PD1_signaling and WP_Cancer_Immunotherapy_by_PD1_blockade. The coespression analyses highlighted more than 600 correlations gene-miRNA-lncRNA for the two above-mentioned genesets. CD4-miR-125a/b and AF131217.1/RP11-362F19.1 are strongly correlated for the first one; whilst, regarding the latter one, CD274/HLA-A with mir-148a/b and PVT1/LINC00665 and JUN with mir-125a/b and AF131217.1/RP11-362F19.1 were found. The validation in cSCC plasma samples evidenced the significant correlation between mir-148a/b and PVT1/LINC00665 and an higher expression of all miRNAs in responders respect to non-responders. The longitudinal study assessing the correlation between miRNA expression and response to cemiplimab is ongoing. Conclusion: Preliminary analysis in pre-therapy plasma samples of cSCC validated the in silico data highlighting the inverse correlation between miR-148a/b and lnc (PVT1 and LINC00665). Further investigation will confirm the role of miR125a/b and miR148a/b as predictors of cemiplimab response. Citation Format: Letizia Porcelli, Simona De Summa, Rossella Fasano, Michele Guida, Tommaso M. Marvulli, Tania Rafaschieri, Giuseppe De Palma, Simona Serratì, Roberta Di Fonte, Ivana De Risi, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti. miRNA lncRNA network associated with response to cemiplimab in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5172.

Abstract 5479: Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers

Abstract High-grade serous ovarian cancer (HGSC) is the most common and aggressive subtype of epithelial ovarian cancer. Importantly, germline mutations in BRCA1/2 give rise to HGSC. Because most HGSC are diagnosed at stage III/IV, outcomes are poor and more effective therapies are needed. Although immune checkpoint inhibitors show promise for a number of cancer types, efficacy has been variable in HGSC. To help provide new clues to the molecular features of HGSC, we set out to elucidate the tumor microenvironment of HGSC using spatial transcriptomics approaches. Specifically, we applied 10x Genomics Visium Spatial Transcriptomics (ST) technology to 48 samples representing primary HGSC tumors from 24 patients, including 15 BRCA1/2 mutated cases and 9 BRCA non-mutated cases. In addition to individual sample analysis, we normalized data from 64,784 total features across all sections and performed an integrated cluster analysis to get an overall picture of the cellular architecture of HGSC, but to also directly investigate differences in the tumor microenvironment based on BRCA mutation status. The resulting 17 integrated clusters were subjected to molecular annotation using GSEA, ESTIMATE, and CIBERSORTx, which revealed feature clusters representing important cell types defined by marker genes. Analysis of the entire dataset identified a primary tumor cluster defined by the expression of known ovarian cancer genes including WFDC2 and “don’t eat me” marker genes CD24 and CD47. However, the predominant tumor cell population in BRCA mutated cases was marked by the expression of MUC1, EPCAM, CLDN3, and CD24, while BRCA non-mutated tumor cell cluster was marked by EFNA1, ID1, LSR, and CD9. Importantly, both groups revealed the presence of a specialized monocyte derived macrophage cluster defined by the expression of LYZ and genes involved in cholesterol metabolism including APOE and APOC1. These lipid-associated macrophages are M2 polarized and shown to be associated with poor outcome. Additional analyses are underway to determine spatial dependencies of various tumor and immunological cell compartments. These data provide novel insights into the HGSC tumor microenvironment that may influence HGSC’s vulnerability to immunological therapies. Citation Format: Jing Qian, Lynda D. Roman, Rania Bassiouni, Seeta Rajpara, Monica Neuman, Varun Khetan, David W. Craig, Joseph W. Carlson, John D. Carpten. Spatially resolved molecular features in the tumor-immune microenvironment of germline BRCA1/2 mutated versus BRCA wild type high grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5479.