Activation Of Immune System Research Articles

Abstract 7611: Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder cancer

Abstract Background: Anti-PD(L)1 immunotherapies have revolutionized oncology by getting durable tumor responses in advanced cancers. Nevertheless, currently approved biomarkers (PD-L1, MSI, TMB) have suboptimal positive/negative predictive values for tumor responses and survival. Aims & Methods: We sought to assess the value of gene expression on circulating blood to predict responses to immunotherapy. We performed total paired-end RNAseq at 20-million reads and analyzed differential gene expressions according to cancer outcomes on baseline frozen whole blood from a cohort of 186 patients prospectively enrolled in the IOPREDI study, a French ancillary cohort of the international multi-center STRONG Phase III trial testing the anti-PD-L1 durvalumab in advanced bladder cancers (NCT03084471). Results: One hundred and sixty four out of the 186 baseline samples generated valuable blood transcriptome data. Thanks to mathematical corrections, all samples were normalized, and the analysis was possible without introducing any bias despite the sample origin from 16 enrolling sites. We first observed that patients with a complete or partial response or a stable disease overexpressed 19 genes, 5 of which are markers of immune cell activation: CXCL8, EOMES, GBP5, GZMA, and GZMH. Conversely, patients with a progressive disease overexpressed 11 genes including CD177, a marker of neutrophil cells, recently associated to immunotherapy resistance. Next, patients with a PFS > 3 months showed an overexpression of 25 genes associated with immune cells activation such as CD8A, CXCL8, EOMES, FASLG, GZM genes, whereas patients with a shorter PFS highly expressed genes of immune cell inhibition: CD177, CD300LG, CD99, and CST7. Finally, patients with an OS > 7 months had also a higher expression of the same previous genes completed with 6 other genes, still indicators of immunity activation (CD3D, CD3E, CD3G, GZMM, IL2RB, and PTGDS). Conclusion: Total RNAseq from RNA directly extracted from whole blood can detect baseline activation of T-cells in patients who will subsequently benefit from anti-PD-L1 immunotherapy. This work shows that RNAseq can detect an immune activation state in circulating blood without specific cell selection. This technique could be used in clinical trials to select for patients prone to benefit from cancer immunotherapies. Citation Format: Corentin Richard, Sandy Chevrier, Aurélien Marabelle, Romain Boidot. Circulating blood RNAseq detects activation of immune system and predicts response to immunotherapy in bladder cancer [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 7611.

Abstract 3735: Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy

Abstract Successful cancer-immunotherapy need to address three critical factors: a) Relieving the immuno-suppressive tumor microenvironment (TME) b) expanding antigen specific, functionally avid effector T cells, c) triggering systemic immunity with a balanced innate-adaptive response for continued effector cell-feeder supply-chain and memory generation. Combinatorial engagement of such multi-elemental components demands smart, engineered immunotherapy systems compared to conventional vaccines. Here, we report an injectable Nano-Immuno-Gel (NIG) that can neutralize immunosuppressive components (e.g., myeloid derived suppressor cells (MDSCs), M2 macrophages (Mϕ) in TME, together with generating strong effector T cells by nano-vaccination, and sustained release of cytokines to enhance systemic immunity against tumor. In a proof-of-concept study, we show that sustained-release of myeloid-suppressive drug from NIG depot efficiently inhibited MDSCs and M2 Mϕ, not only in TME, but also in the circulation and in peripheral systems, thus creating a conducive, hot TME infiltrated with CD8 effector cells. Follow-up antigen vaccination with novel nano-adjuvant enhanced DC-T cell engagement and sustained IL15 release from NIG provided systemic NK/T cell activation, rendering significant control of the tumor growth. Our data demonstrate the potential of rationally engineered multi-functional nano-immuno-gels (NIG) to combine sequential neutralization of the suppressive TME, antigen vaccination, and concurrent systemic immune activation for highly effective combinatorial cancer immunotherapy. Citation Format: Anjali Kozhissery Sunilkumar, Margaux Salvi, Saira Nujoom Mohammed, Zahara Thaivalappil Zakkariya, Alejandra Gomez Cadena, Shalin Chappan, Sreedevi Panachithanathu Radhakrishnan, Maneesh Manohar, Pavithran Keechilat, Shantikumar Nair, Pedro Romero, Camilla Jandus, Manzoor Koyakutty. Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy [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 3735.

Abstract 4077: T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability

Abstract Engagement of T cell cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-immunocytokines, based on molecular architectures generated by a variant of DNA recombinant technologies, have recently entered the clinic. Earlier we have demonstrated how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan1, can be applied for attachment of various cytokines, including RLI or IL-15, without prior antibody engineering. The immunostimulatory activity of these GlycoConnect™ immune cell engagers (GC™-ICEs) can be modulated by tailoring linker design and payload stoichiometry. In this presentation, we demonstrate the GC™-ICE with either IL-15 or RLI can be applied to selective targeting of T cells, based on PD-1-selective binding and activation, using either protease-sensitive or non-cleavable linkers. We will show how such T cell targeting can be achieved leading to significant tumor volume reductions in syngeneic mouse models. Moreover, we have found that the GC-ICE™ can be applied without inducing systemic immune activation, thereby displaying a promising therapeutic index. In vitro and in vivo studies will be presented to showcase the biological activity of these GC™-ICEs in comparison to conventional immunocytokines obtained via genetic engineering.1Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14, DOI: 10.1080/19420862.2022.2078466. Citation Format: Remon van Geel, Mick Verhagen, Elias Post, Willem Vugs, Sorraya Popal, Sander van Berkel, Floris van Delft. T cell targeting with PD-1-selective immune cell engagers based on GlycoConnect™ (GC™-ICEs) show excellent efficacy and tolerability [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 4077.

Abstract 2129: Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer

Abstract Background: A phase 1b/2 study (NCT05218889) of surufatinib combined with camrelizumab, nab-paclitaxel, and S-1 (NASCA) as first-line therapy for metastatic pancreatic adenocarcinoma has shown promising results, potentially overcoming the limitations of current pancreatic immunotherapies. Animal studies are underway to further explore the synergistic effects and mechanisms of this combined therapeutic approach. Methods: Genetically engineered KPC mouse cells were used to establish a subcutaneous transplantation tumor model in female mice, which were then divided into control group, AG group (nab-paclitaxel + gemcitabine), and NASCA group. Tumor metrics were recorded until euthanasia after 21 days. Blood and tumor samples were analyzed using Flow Cytometry. Results: Compared with the control group, the NASCA and AG groups demonstrated tumor volume reductions of 14.7% (p=0.172) and -0.4% (p=0.972) on day 7, respectively. At day 14, the reductions were 48.8% and 29.9% (p<0.001*, p=0.002*). At day 21, the reductions were 37.4% and 21.5% (p=0.001*, p=0.144). The tumor growth inhibitions (TGIs) for NASCA and AG group were 56.7% (p<0.001*) and 21.2% (p=0.36), respectively. Compare to AG group, the tumor volume reduction in NASCA group were 15.1% (p=0.050*), 26.9% (p=0.001*) and 20.3% (p=0.116), respectively. And the TGIs for NASCA group compare AG group was 45.0% (p=0.020*). Distinguishingly, the NASCA group, when compared to the AG group, had a heightened proportion of M1 macrophages (28.5% vs. 15.5%, p=0.019*), mCD68+ Macrophages (99.7% vs. 99.1%, p=0,014*) and mPD-1+/mCD8+ T cells (24.8% vs. 9.8%, p=0.03*). Furthermore, T-regulatory cells (T-regs) in peripheral blood demonstrated uniformity across the groups, were no statistically. RNA-seq analysis revealed that the NASCA significantly suppressed multiple anti-angiogenic pathways while enhancing the cytokine pathway (p=0.005*), indicating potential immune system activation. Conclusion: The NASCA group outperformed the AG group in controlling tumor growth and early tumor shrinkage, potentially due to macrophage polarization regulation. Further research is vital to understand the benefits of integrating targeted therapy, immunotherapy, and chemotherapy for pancreatic cancer. Citation Format: Nan Zhang, Ru Jia, Guanghai Dai. Efficacy and underlying mechanisms of surufatinib combined with PD-1 monoclonal antibody and chemotherapy in pancreatic cancer [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 2129.

Abstract 2640: HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies

Abstract MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for its histone methyl transferase (HMT) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in the discovery of anti-cancer drugs for both leukemia and solid tumors. We recently identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. HBI-2375 showed potent inhibition of WDR5 (IC50: 4.48nM) in biochemical assay and inhibited MV4-11 cellular proliferation (average IC50: 3.17µM) in CTG assays. In addition, HBI-2375 was stable in liver S9 and whole blood, with moderate to high plasma protein binding rates in multiple species, and acceptable hERG (IC50: 17µM). Furthermore, HBI-2375 displayed reasonable oral PK properties (Cmax, T1/2, AUC, and F%) in mouse, rat and dog and showed good safety profile in GLP tox studies. In pharmacology studies HBI-2375 showed significant dose dependent anti-tumor activity in MV4-11 AML model along with reduction in methylation of H3K4 in the tumors harvested from the treated animals demonstrating the targeted disruption of HMT activity in cancer cells by HBI-2375. Furthermore HBI-2375 in combination with PD-1 mAb significantly inhibited tumor growth in MC38, colorectal tumor model, and in 3LL lung carcinoma syngeneic tumor models. Flow cytometry and IHC showed significant increase in the infiltration of CD8+ CTLs in the combination group further providing immune-driven mechanisms for greater efficacy of combination therapy. Gene expression analysis also identified genes that are involved in promoting immune system activity in the combination group. Tissue distribution studies also showed greater accumulation of HBI-2375 in brain tissue indicative of a potential to target glioma and glioblastoma in clinical studies. Therefore, HBI-2375 represents a first-in-class MLL1-WDR5 inhibitor with promising characteristics for future testing in the clinic. Citation Format: Farbod Shojaei, Che Fang, Jill M. Ricono, Mireille Gillings. HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies [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 2640.

Abstract 5662: PDCD1 and CD48 significantly impact cancer recurrence and survival in pediatric acute lymphoblastic leukemia

Abstract Introduction: Immune checkpoints (ICPs) play a critical role in modulating the immune response, maintaining self-tolerance, and preventing excessive immune system activation. Dysregulation of immune checkpoints has been implicated in cancer progression and treatment resistance. In this study, we aimed to screen for dysregulated immune checkpoint genes that might be associated with cancer recurrence in pediatric acute lymphoblastic leukemia (ALL) following a course of cancer treatment. We hypothesized that certain ICPs would be significantly dysregulated in relapsed ALL patients, potentially providing insights into the underlying mechanisms driving therapy resistance and disease recurrence. Methods: 51 ICP genomic data (gene expression, copy number alterations (CNAs), and mutation) of133 patients with relapse information [relapse-free (n=29) and relapsed (n=104)] extracted from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) were examined in the study. Patient’s t-test (p-value < 0.05) was used to identify significant genetic factors between relapse-free and relapsed patients. Free and overall survival analyses were performed using log-rank test (p-value < 0.05) based on patient gene expression profiles. Results: Among the 51 genes examined, PDCD1, PVR, CD70, and CD48 were significantly upregulated in relapsed patients compared with relapse-free patients (P < 0.05). No significant CNAs nor mutations were detected in these four genes. Patients with high expression profiles of PDCD1 and CD48 at diagnosis were 1.71 and 1.47 more likely to relapse compared to patients with low expression profiles, respectively (P < 0.05). Furthermore, the upregulation of PDCD1 (P= 0.0004, HR= 1.972) and CD48 (P= 0.0344, HR= 1.533) demonstrated significantly increased mortality rates in patients following treatment, as indicated by overall survival analyses. Conclusion: The upregulation of PDCD1 and CD48 was significantly associated with relapse and survival of ALL patients. Promisingly, these two ICPs can potentially be used as prognostic biomarkers for relapse risk and rationale for alternative therapeutic strategies. Our study suggests that targeting PDCD1 and CD48 might be beneficial in enhancing the treatment efficiency and thereby reducing the recurrence risk. The study was funded by the Deputyship for Research and Innovation, Ministry of Education, Saudi Arabia (DRI-KSU-1273). Citation Format: Shatha Fawaz Alotaibi, Lames Abuhadi, Noura Alolyani, Moureq R. Alotaibi, Ali R. Alhoshani, Homood As Sobeai. PDCD1 and CD48 significantly impact cancer recurrence and survival in pediatric acute lymphoblastic leukemia [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 5662.

When Our Best Friend Becomes Our Worst Enemy: The Mitochondrion in Trauma, Surgery, and Critical Illness.

Common for major surgery, multitrauma, sepsis, and critical illness, is a whole-body inflammation. Tissue injury is able to trigger a generalized inflammatory reaction. Cell death causes release of endogenous structures termed damage associated molecular patterns (DAMPs) that initiate a sterile inflammation. Mitochondria are evolutionary endosymbionts originating from bacteria, containing molecular patterns similar to bacteria. These molecular patterns are termed mitochondrial DAMPs (mDAMPs). Mitochondrial debris released into the extracellular space or into the circulation is immunogenic and damaging secondary to activation of the innate immune system. In the circulation, released mDAMPS are either free or exist in extracellular vesicles, being able to act on every organ and cell in the body. However, the role of mDAMPs in trauma and critical care is not fully clarified. There is a complete lack of knowledge how they may be counteracted in patients. Among mDAMPs are mitochondrial DNA, cardiolipin, N-formyl peptides, cytochrome C, adenosine triphosphate, reactive oxygen species, succinate, and mitochondrial transcription factor A. In this overview, we present the different mDAMPs, their function, release, targets, and inflammatory potential. In light of present knowledge, the role of mDAMPs in the pathophysiology of major surgery and trauma as well as sepsis, and critical care is discussed.

Fitness age outperforms body mass index in differentiating aging patterns and health risk profiles of healthy adults aged 51-80years.

Physical fitness has been extensively shown to strongly associate with general health status and major health risks. Here we tested the ability of a novel estimate of fitness age (FitAge) to differentiate aging trajectories.This study aimed at (1) testing the ability of FitAge to differentiate aging patterns among decelerated, normal, and accelerated agers in selected health domains, (2) estimating the risk for developing major health issues depending on the aging trajectory, and (3) comparing FitAge to body mass index (BMI) categorization in differentiating healthy from unhealthy aging patterns.A total of 176 volunteers participated in this cross-sectional study. Participants underwent clinical screening and a comprehensive assessment of body composition, nutritional and health-related status, cognitive functioning, and haematochemical analyses with routine tests, oxidative stress, and inflammation markers. Scores for major health risks were also computed.FitAge outperformed BMI in estimating major health risk scores and was able to differentiate decelerated from normal and accelerated agers for health risk profile and several physiological domains. Body composition, immune system activation, and inflammation markers emerged as those variables flagging the largest differences between decelerated and accelerated aging patterns.The novel estimate of biological aging can accurately differentiate both in women and men decelerated from accelerated agers in almost all the domains scrutinized. Overall, decelerated aging is linked to positively oriented features which associate with reduced risk of developing major health issues.The present findings have potential relevance and practical implications to identify individuals at higher risk of accelerated aging according to their FitAge estimated via simple and cost-effective motor tests.

Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity.

Treatment for higher-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti-tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time-to-recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG-induced trained immunity modulates anti-tumor immune responses. Compared with intravesical BCG, which led to a tumor-promoting immune microenvironment, intravenous BCG resulted in an anti-tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid-derived suppressor cells. Polarization toward anti-tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre-treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre-treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co-instillation of BCG-trained macrophages with ovalbumin-expressing bladder tumor cells increased the proportion of tumor-specific CTLs. Furthermore, BCG-trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti-tumor responses, and that BCG-induced trained immunity is important in driving anti-tumor adaptive immunity.

Identification of prognostic factors for survival in patients with metastatic gastric adenocarcinoma in a Mexican population

Introduction and aimsGastric adenocarcinoma is among the high-ranking tumors, with respect to frequency and mortality, worldwide. The inflammatory process and immune system activity are associated with oncologic control. Our aim was to identify whether the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and other variables are prognostic factors for survival in patients with metastatic gastric cancer in a Mexican population. Material and methodsPatients diagnosed with metastatic gastric adenocarcinoma, hospitalized within the time frame of December 2011 to 2021, were analyzed. The NLR, PLR, and albumin and hemoglobin levels obtained from blood samples were calculated. Functional status (ECOG and Karnofsky), sex, histology, and the presence of signet ring cells were also considered possible prognostic factors. Each factor’s prognostic value for overall survival was determined through univariate and multivariate analyses. ResultsThe study included 956 patients diagnosed with metastatic gastric cancer, of whom 494 (51.7%) were men and 462 (48.3%) were women. The main histologic finding was diffuse adenocarcinoma (n = 619, 64.7%), followed by intestinal adenocarcinoma (n = 293, 30.6%), and the presence of signet ring cells was found in 659 (68.9%) patients. Diagnostic laparoscopy was performed on 238 patients (24.9%) to confirm peritoneal carcinomatosis. The multivariate analysis showed that an NLR above 3.2 (HR 1.51, 95% CI 1.27–1.8; p < 0.001), albumin below 3.5 g/dl (HR 1.25, CI 1.06–1.47; p = 0.006), and an ECOG performance status of 2 or higher (HR 1.39, CI 1.10–1.76; p = 0.005) were independent factors that predicted a lower survival rate, whereas a Karnofsky score above 70% (HR 0.69, CI 0.53–0.91; p = 0.008) was associated with a better survival rate. Lastly, the PLR was not statistically significant in the multivariate analysis. ConclusionsThe NLR, nutritional status assessed through albumin measurement, and functional status can act as independent prognostic survival factors in hospitalized Mexican patients diagnosed with metastatic gastric adenocarcinoma and be taken into account during therapeutic decision-making.

Gut Microbiota and Inflammation Modulation in a Rat Model for Ulcerative Colitis after the Intraperitoneal Administration of Apigenin, Luteolin, and Xanthohumol.

Ulcerative colitis (UC) is a chronic inflammatory disorder affecting the colon, with symptomatology influenced by factors including environmental, genomic, microbial, and immunological interactions. Gut microbiota dysbiosis, characterized by bacterial population alterations, contributes to intestinal homeostasis disruption and aberrant immune system activation, thereby exacerbating the inflammatory state. This study assesses the therapeutic efficacy of intraperitoneal (IP) injected flavonoids (apigenin, luteolin, and xanthohumol) in the reduction of inflammatory parameters and the modulation of the gut microbiota in a murine model of ulcerative colitis. Flavonoids interact with gut microbiota by modulating their composition and serving as substrates for the fermentation into other anti-inflammatory bioactive compounds. Our results demonstrate the effectiveness of luteolin and xanthohumol treatment in enhancing the relative abundance of anti-inflammatory microorganisms, thereby attenuating pro-inflammatory species. Moreover, all three flavonoids exhibit efficacy in the reduction of pro-inflammatory cytokine levels, with luteolin strongly demonstrating utility in alleviating associated physical UC symptoms. This suggests that this molecule is a potential alternative or co-therapy to conventional pharmacological interventions, potentially mitigating their adverse effects. A limited impact on microbiota is observed with apigenin, and this is attributed to its solubility constraints via the chosen administration route, resulting in its accumulation in the mesentery.

Interpersonal violence exposure and inflammation during adolescence and young adulthood

Exposure to violence increases young peoples’ risk of developing mental and physical health problems. Chronic stress-related upregulation of innate immune system activity and the development of low-grade inflammation may partially underlie this health risk. However, much of the previous research has been limited to cross-sectional studies utilizing between-person analytic designs, susceptible to confounding by unmeasured factors. In this six-wave panel study of N=157 female adolescents and young adults, we tested within-person associations between interpersonal violence exposure and multiple measures of inflammatory activity. Ex vivo culture studies suggested that participants’ immune cells were more reactive to microbial stimulation and less sensitive to inhibition by glucocorticoids after violence. Numbers of circulating monocyte cells increased after violence, but serum levels of interleukin-6 and c-reactive protein did not. Findings from this within-person analysis suggest that violence exposure up-regulates innate immune system activity during adolescence and young adulthood in ways that may increase mental and physical health risk.

Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

Evaluation of immunomodulatory (humoral as well as cell-mediated) and cytokines (TNF-α & IL-10) regulating potential of Neolamarckia cadamba fruit extract in Wistar albino rats.

Current work has been designed to investigate the immunomodulatory efficacy with particular reference to humoral, cell-mediated and cytokine-modulating potential of hot aqueous extract of Neolamarckia cadamba (HAENC) fruits in Wistar albino rats. The effect of different concentrations of HAENC fruits over cell-mediated immune response was assessed using six groups (Gp-I as control, Gp-II with 20µg/mL, Gp-III with 50µg/mL, Gp-IV with 100µg/mL, Gp-V with 250µg/mL, and Gp-VI with 500µg/mL) of Wistar albino rats having six animals in each. The amount of tumor necrosis factor-α (TNF-α) and interleukin (IL)-10 was measured by sandwich ELISA with different concentrations of HAENC (50-500µg/mL) in splenocyte culture supernatant and their expression was determined by qRT-PCR Humoral immune response was determined by measuring the serum antibody titer of Wistar albino rats against Salmonella typhimurium 'O' antigen using four groups containing six animals each (Gp-I as control, Gp II, III & IV were respectively fed orally with 125, 250, and 500mg/Kg body weight using HAENC fruits). LC-MS analysis suggested the presence of cadambine, chlorogenic acid, cadambagenic acid, stearic acid, octadecanoic acid ethyl ether, and 7-hydroxy-5,2'-4'-trimethoxyflavonon in the extract based on their m/z ratio. The result suggested significant (p < 0.01) dose-dependent proliferation of Concanavalin A (Con A)-treated splenocytes, depicting cell-mediated immunostimulatory potential of HAENC fruits. A dose-dependent significant decrease (p < 0.01) was found in the amount of TNF-α and IL-10 was found to increase significantly (p < 0.01) as extract concentrations increased. TNF-α and IL-10 expressions were confirmed at the molecular level by qRT-PCR analysis of mRNA transcripts of TNF-α and IL-10 genes. Fold expression of TNF-α and IL-10 gene was 0.197 and 3.58 at 250µg/mL, 0.02 and 20.11 at 500µg/mL concentrations of HAENC respectively in comparison to control. Serum antibody titer was significantly increased (p < 0.01) in animals fed with different doses of HAENC fruits. The present study suggested the anti-inflammatory effect of HAENC fruits which also influences the networking of cytokines, implying that it may play a role in regulating the activity of the host's immune system and can serve as a potent herbal drug with immuno-stimulatory potential.

PANoptosis-related genes function as efficient prognostic biomarkers in colon adenocarcinoma.

PANoptosis is a newly discovered cell death type, and tightly associated with immune system activities. To date, the mechanism, regulation and application of PANoptosis in tumor is largely unknown. Our aim is to explore the prognostic value of PANoptosis-related genes in colon adenocarcinoma (COAD). Analyzing data from The Cancer Genome Atlas-COAD (TCGA-COAD) involving 458 COAD cases, we concentrated on five PANoptosis pathways from the Molecular Signatures Database (MSigDB) and a comprehensive set of immune-related genes. Our approach involved identifying distinct genetic COAD subtype clusters and developing a prognostic model based on these parameters. The research successfully identified two genetic subtype clusters in COAD, marked by distinct profiles in PANoptosis pathways and immune-related gene expression. A prognostic model, incorporating these findings, demonstrated significant predictive power for survival outcomes, underscoring the interplay between PANoptosis and immune responses in COAD. This study enhances our understanding of COAD's genetic framework, emphasizing the synergy between cell death pathways and the immune system. The development of a prognostic model based on these insights offers a promising tool for personalized treatment strategies. Future research should focus on validating and refining this model in clinical settings to optimize therapeutic interventions in COAD.

Correlation between neutrophil to lymphocyte ratio and disease activity in patients with rheumatoid arthritis.

Objective: To figure out correlation between neutrophils to lymphocyte ratio in rheumatoid arthritis and its relationship with the disease severity. Study Design: Prospective study. Setting: Department of Rheumatology Fauji Foundation Hospital, Rawalpindi, Pakistan. Period: July 1st to December 31st, 2021. Material &amp; Methods: Study population included rheumatoid arthritis patients fulfilling American college for rheumatology criteria. On the basis of disease activity score-28 (DAS-28), the subjects were categorised into active and remission groups. The control group consisted of healthy age and gender matched subjects. Relationship between neutrophils to lymphocytes ratio with disease activity was analyzed. Data was analysed using SPSS 21. Results: 140 patients with RA were evaluated along with 70 healthy control subjects. NLR was higher in active RA (1.99±0.84) as compared to RA with remission (1.76±0.41) and controls (1.77±0.79). p value&lt;0.05 was obtained which was statistically significant. NLR is significantly correlated with CDAI and SDAI (r=0.24, p=0.04 each). CRP and ESR were also significantly higher in active RA patients compared to those in remission (p&lt;0.005 and p&lt;0.00 respectively) and control group. Conclusion: The neutrophil to lymphocyte ratio is a measure derived from a simple blood test. An elevated NLR is often considered an indicator of systemic inflammation. High NLR values may suggest increased inflammation and immune system activation, which are key features of RA. NLR may serve as a less expensive and easily accessible marker to detect inflammation in RA. It can be utilized in future as disease assessment tool.

A Synthetic Multivalent Lipopeptide Derived from Pam3CSK4 with Irreversible Influenza Inhibition and Immuno-Stimulating Effects.

The activation of the host adaptive immune system is crucial for eliminating viruses. However, influenza infection often suppresses the innate immune response that precedes adaptive immunity, and the adaptive immune responses are typically delayed. Dendritic cells, serving as professional antigen-presenting cells, have a vital role in initiating the adaptive immune response. In this study, an immuno-stimulating antiviral system (ISAS) is introduced, which is composed of the immuno-stimulating adjuvant lipopeptide Pam3CSK4 that acts as a scaffold onto which it is covalently bound 3 to 4 influenza-inhibiting peptides. The multivalent display of peptides on the scaffold leads to a potent inhibition against H1N1 (EC50=20nM). Importantly, the resulting lipopeptide, Pam3FDA, shows an irreversible inhibition mechanism. The chemical modification of peptides on the scaffold maintains Pam3CSK4's ability to stimulate dendritic cell maturation, thereby rendering Pam3FDA a unique antiviral. This is attributed to its immune activation capability, which also acts in synergy to expedite viral elimination.

Significance of Spread Through Air Spaces and Vascular Invasion in Early-stage Adenocarcinoma Survival: A Comprehensive Clinicopathologic Study of 427 Patients for Precision Management.

Spread through air spaces (STAS) is a novel invasive pattern of lung cancer associated with poor prognosis in non-small cell cancer (NSCLC). We aimed to investigate the incidence of STAS in a surgical series of adenocarcinomas (ADCs) resected in our thoracic surgery unit and to identify the association of STAS with other clinicopathological characteristics. We retrospectively enrolled patients with stage cT1a-cT2b who underwent resection between 2016 and 2022. For each case, a comprehensive pathologic report was accessible which included histotype, mitoses, pleural invasion, fibrosis, tumor infiltrating lymphocytes, necrosis, inflammation, vascular and perineural invasion, as well as STAS. PD-L1 expression was also investigated. A total of 427 patients with ADCs underwent surgery. Regarding overall survival (OS), no significant difference was observed between the STAS positive (STAS+) and STAS negative (STAS-) groups ( P =0.44). However, vascular invasion (VI) was associated with a poorer survival probability ( P =0.018). STAS+/VI+ patients had tendentially worse survival compared with STAS+/VI- ( P =0.089). ADCs with pathologic evidence of immune system (IS) activation (TILs>10% and PD-L1≥1) demonstrated significantly increased OS compared with ADCs with no IS and VI. In terms of recurrence rate, no statistical differences were found between the STAS+ and STAS- samples ( P =0.2). VI was also linked to a significantly elevated risk of recurrence ( P =0.0048). Our study suggests that in resected early-stage ADCs, STAS+ does not seem to influence recurrence or mortality. VI was instead an adverse pathologic prognostic factor for both survival and recurrence, whereas IS seemed to be protective.

Exploring the emerging bidirectional association between inflamm-aging and cellular senescence in organismal aging and disease.

There is strong evidence that most individuals in the elderly population are characterized by inflamm-aging which refers to a subtle increase in the systemic pro-inflammatory environment and impaired innate immune activation. Although a variety of distinct factors are associated with the progression of inflamm-aging, emerging research is demonstrating a dynamic relationship between the processes of cellular senescence and inflamm-aging. Cellular senescence is a recognized factor governing organismal aging, and through a characteristic secretome, accumulating senescent cells can induce and augment a pro-inflammatory tissue environment that provides a rationale for immune system-independent activation of inflamm-aging and associated diseases. There is also accumulating evidence that inflamm-aging or its components can directly accelerate the development of senescent cells and ultimately senescent cell burden in tissues in a likely vicious inflammatory loop. The present review is intended to describe the emerging senescence-based molecular etiology of inflamm-aging as well as the dynamic reciprocal interactions between inflamm-aging and cellular senescence. Therapeutic interventions concurrently targeting cellular senescence and inflamm-aging are discussed and limitations as well as research opportunities have been deliberated. An effort has been made to provide a rationale for integrating inflamm-aging with cellular senescence both as an underlying cause and therapeutic target for further studies.

Vaccines in cardiology, an underutilized strategy to reduce the residual cardiovascular risk.

Cardiovascular diseases stand as the leading cause of mortality among adults globally. For decades, comprehensive evidence has underscored the correlation between infections, particularly those involving the respiratory system, and an elevated risk of cardiovascular and cerebrovascular events, as well as all-cause mortality. The mechanisms through which infections heighten cardiovascular events are intricate, encompassing immune system activation, systemic inflammation, hypercoagulable states, sympathetic system activation, and increased myocardial oxygen demand. Respiratory infections further contribute hypoxemia to this complex interplay. These mechanisms intertwine, giving rise to endothelial dysfunction, plaque ruptures, myocardial depression, and heart failure. They can either instigate de novo cardiovascular events or exacerbate pre-existing conditions. Compelling evidence supports the safety of influenza, pneumococcal, herpes zoster, COVID-19 and respiratory syncytial virus vaccines in individuals with cardiovascular risk factors or established cardiovascular disease. Notably, the influenza vaccine has demonstrated safety even when administered during the acute phase of a myocardial infarction in individuals undergoing angioplasty. Beyond safety, these vaccinations significantly reduce the incidence of cardiovascular events in individuals with an augmented cardiovascular risk. Nevertheless, vaccination rates remain markedly suboptimal. This manuscript delves into the intricate relationship between infections and cardiovascular events. Additionally, we highlight the role of vaccinations as a tool to mitigate these occurrences and reduce residual cardiovascular risk. Finally, we emphasize the imperative need to optimize vaccination rates among individuals with heart diseases.