Biomarkers Of Immune Response Research Articles

Association of intestinal bacteria with immune activation in a cohort of healthy adults.

Interactions among intestinal bacteria and the immune system contribute to the maintenance of a functional intestinal barrier in healthy individuals, and possibly to systemic immune activity. We hypothesized that intestinal bacteria would be associated with systemic biomarkers of innate and adaptive immune responses in healthy adults. 79 immune function markers were subjected to factor analysis resulting in 17 Immune Factors (IFs), each composed of 2-10 immune variables. Bacterial taxa from stool samples were identified at the family and genus levels by 16S rRNA amplicon sequence analysis and their read counts and relative abundances were utilized in a multiple linear regression model to identify microbial taxa associated with the IFs. A total of 10 significant associations were identified between bacterial taxa and IFs. The family Rikenellaceae showed a positive association with innate IF5 (including 5 chemokines, 2 cytokines, 2 adhesion molecules, and the macrophage metabolite neopterin) and a negative association with adaptive IF4 (including T-cells with activation marker HLA-DR). Additionally, Pseudomonadaceae and its genus Pseudomonas showed a negative relationship with innate IF5, and adaptive IF13 (including T-cell cytokines IL-10, IL-17, and IFN-γ) was negatively associated with Butyrivibrio and positively associated with Slackia. These associations suggest ongoing interactions between gut bacteria and the systemic immune system in healthy adults. The association of these taxa with the IFs may result from specific microbial-immune system interactions that play a role in maintenance of a healthy barrier integrity in our cohort of healthy adults. IMPORTANCE Chronic inflammation may develop over time in healthy adults as a result of a variety of factors, such as poor diet directly affecting the composition of the intestinal microbiome, or by causing obesity, which may also affect the intestinal microbiome. These effects may trigger the activation of an immune response that could eventually lead to an inflammation-related disease, such as colon cancer. Before disease develops it may be possible to identify subclinical inflammation or immune activation attributable to specific intestinal bacteria normally found in the gut that could result in future adverse health impacts. In the present study, we examined a group of healthy men and women across a wide age range with and without obesity to determine which bacteria were associated with particular types of immune activation to identify potential preclinical markers of inflammatory disease risk. Several associations were found that may help develop dietary interventions to lower disease risk.

A-229 Immune Biomarkers Associated with COVID-19 Disease Severity in an Urban, Hospitalized Population

Abstract Background We sought to identify immune biomarkers associated with severe Coronavirus disease 2019 (COVID-19) in patients admitted to a large public county hospital during the early phase of the SARS-CoV-2 pandemic. We hypothesized that we could identify clinically relevant immune markers at the time of initial hospital admission that could be used to predict the course of COVID-19 illness. Methods The study population consisted of SARS-CoV-2 positive patients admitted for COVID-19 (n = 58) or controls (n = 14) at the Los Angeles County University of Southern California Medical Center between April-December 2020. Immunologic markers including chemokine/cytokines (IL-6, IL-8, IL-10, IP-10, MCP-1, TNFα) and serologic markers against SARS-CoV-2 antigens (including spike subunits S1 and S2, receptor binding domain (RBD), and nucleocapsid (N)) were assessed in serum collected on the day of admission using custom MILLIPLEX® immunoassay panels. Result values were computed using mean fluorescent intensity in individual samples fit to a standard curve using a 5PL logistic formula with power law variance. Comparison of patient demographic, clinical, cytokines and immunoglobulins characteristics between mild vs moderate/severe COVID-19 groups were conducted using Wilcoxon tests for continuous variables and Chi-square tests for categorical variables. Linear support vector machine models were fitted to perform the binary classification task of predicting mild vs moderate/severe COVID-19 using the python library scikit-learn. Results SARS-CoV-2 antibody levels were significantly elevated in patients with the highest COVID-19 disease severity, with IgM S1, IgG N, IgG RBD, IgG S1, and IgG S2 showing statistical significance between mild vs moderate/severe disease group medians (P = 0.037, 0.032, 0.007, 0.003, and 0.015, respectively). Of the chemokines/cytokines tested, only IP-10 showed significance across the disease groups (medians 640.8 pg/mL in mild, 493.3 pg/mL in moderate/severe, and 259.9 pg/mL in control, overall P = 0.005). The linear support vector machine model achieved an accuracy of 64% and an AUROC of 0.81 in predicting COVID-19 severity status. The most important clinical variables for predicting disease severity were white blood cell count, diastolic blood pressure, and platelet count, while the most important serologic markers were IgG anti-SARS-CoV-2 N, S1, S2, TNF-α, IP-10, and IL-10. Conclusion Our results suggest that IP-10 and anti-SARS-CoV-2 antibody measurements could be useful to identify patients most likely to experience the most severe forms of the disease. Strengths of this study include a focus on a racially and ethnically diverse patient population and a combined analysis of both cytokine/chemokine and immune response (antibody) biomarkers. However, we emphasize that our subjects were enrolled at a time before widespread vaccination against SARS-CoV-2.

Imaging and monitoring of granzyme B in the immune response.

Significant progress has been made in tumor immunotherapy that uses the human immune response to kill and remove tumor cells. However, overreactive immune response could lead to various autoimmune diseases and acute rejection. Accurate and specific monitoring of immune responses in these processes could help select appropriate therapies and regimens for the patient and could reduce the risk of side effects. Granzyme B (GzmB) is an ideal biomarker for immune response, and its peptide substrate could be coupled with fluorescent dyes or contrast agents for the synthesis of imaging probes activated by GzmB. These small molecules and nanoprobes based on PET, bioluminescence imaging, or fluorescence imaging have proved to be highly GzmB specific and accuracy. This review summarizes the design of different GzmB-responsive imaging probes and their applications in monitoring of tumor immunotherapy and overreactive immune response. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

The associations between dietary fibers intake and systemic immune and inflammatory biomarkers, a multi-cycle study of NHANES 2015-2020.

In recent years, there has been considerable growth in abnormal inflammatory reactions and immune system dysfunction, which are implicated in chronic inflammatory illnesses and a variety of other conditions. Dietary fibers have emerged as potential regulators of the human immune and inflammatory response. Therefore, this study aims to investigate the associations between dietary fibers intake and systemic immune and inflammatory biomarkers. This cross-sectional study used data from the National Health and Nutrition Examination Survey (2015-2020). Dietary fibers intake was defined as the mean of two 24-h dietary recall interviews. The systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), red blood cell distribution width-to-albumin ratio (RA), ferritin, high-sensitivity C-reactive protein (hs-CRP), and white blood cell (WBC) count were measured to evaluate systemic immune and inflammatory states of the body. The statistical software packages R and EmpowerStats were used to examine the associations between dietary fibers intake and systemic immune and inflammatory biomarkers. Overall, 14,392 participants were included in this study. After adjusting for age, gender, race, family monthly poverty level index, alcohol consumption, smoking status, vigorous recreational activity, body mass index, hyperlipidemia, hypertension, diabetes, and dietary inflammatory index, dietary fibers intake was inversely associated with SII (β = -2.19885, 95% CI: -3.21476 to -1.18294, p = 0.000248), SIRI (β = -0.00642, 95% CI: -0.01021 to -0.00263, p = 0.001738), NLR (β = -0.00803, 95% CI: -0.01179 to -0.00427, p = 0.000284), RA (β = -0.00266, 95% CI: -0.00401 to -0.00131, p = 0.000644), ferritin (β = -0.73086, 95% CI: -1.31385 to -0.14787, p = 0.020716), hs-CRP (β = -0.04629, 95% CI: -0.0743 to -0.01829, p = 0.002119), WBC (β = -0.01624, 95% CI: -0.02685 to -0.00563, p = 0.004066), neutrophils (β = -0.01346, 95% CI: -0.01929 to -0.00764, p = 0.000064). An inverse association between dietary fibers and PLR was observed in the middle (β = -3.11979, 95% CI: -5.74119 to -0.4984, p = 0.028014) and the highest tertile (β = -4.48801, 95% CI: -7.92369 to -1.05234, p = 0.016881) and the trend test (βtrend = -2.2626, 95% CI: -3.9648 to -0.5604, Ptrend = 0.0150). The observed associations between dietary fibers intake and SII, SIRI, NLR, RA, ferritin, hs-CRP, WBC, and neutrophils remained robust and consistent in the sensitivity analysis. No significant interaction by race was found. Dietary fibers intake is associated with the improvement of the parameters of the immune response and inflammatory biomarkers, supporting recommendations to increase dietary fibers intake for enhanced immune health.

Evaluation of neopterin levels and kynurenine pathway in patients with acute coronary syndrome.

Coronary atherosclerosis is the leading cause of coronary artery disease. Several investigations have indicated that tear-sensitive plaques contain macrophages and T cells. Neopterin is an essential cellular immune response biomarker. The main goal of this study was to see if there were any changes in biomarkers like unconjugated pteridines, neopterin, and biopterin, as well as kynurenine pathway enzymes like indoleamine 2,3-dioxygenase (IDO), which catalyzes the rate-limiting step in tryptophan degradation, in patients with the acute coronary syndrome (ACS) caused by angiographic atherosclerosis. High-performance liquid chromatography was used to determine the amounts of neopterin, biopterin, and creatinine in urine samples, as well as tryptophan and kynurenine in serum samples. The enzyme-linked immunosorbent assay was used to assess the amounts of neopterin in serum samples. The measured parameters were evaluated between ACS patients and controls. The measured levels of neopterin, biopterin and the kynurenine to tryptophan ratio reflecting IDO activity, and the specifically known biomarkers such as cardiac troponin, creatine kinase, myoglobin, and natriuretic peptides are statistically higher in ACS patients compared to control subjects. On the other hand, the measured parameters are inadequate to classify the conventional kinds of ACS, ST-elevation- and non-ST-elevation- myocardial infarction. The study found that determining and using neopterin and IDO parameters as biomarkers in individuals with the ACS can support traditional biomarkers. However, it can be concluded that evaluating pteridine biomarkers solely have no privilege to clinical findings in ACS diagnosis and classification.

Associations of Multiparametric Breast MRI Features, Tumor-Infiltrating Lymphocytes, and Immune Gene Signature Scores Following a Single Dose of Trastuzumab in HER2-Positive Early-Stage Breast Cancer.

Dynamic biomarkers that permit the real-time monitoring of the tumor microenvironment response to therapy are an unmet need in breast cancer. Breast magnetic resonance imaging (MRI) has demonstrated value as a predictor of pathologic complete response and may reflect immune cell changes in the tumor microenvironment. The purpose of this pilot study was to investigate the value of breast MRI features as early markers of treatment-induced immune response. Fourteen patients with early HER2+ breast cancer were enrolled in a window-of-opportunity study where a single dose of trastuzumab was administered and both tissue and MRIs were obtained at the pre- and post-treatment stages. Functional diffusion-weighted and dynamic contrast-enhanced MRI tumor measures were compared with tumor-infiltrating lymphocytes (TILs) and RNA immune signature scores. Both the pre-treatment apparent diffusion coefficient (ADC) and the change in peak percent enhancement (DPE) were associated with increased tumor-infiltrating lymphocytes with trastuzumab therapy (r = -0.67 and -0.69, p < 0.01 and p < 0.01, respectively). Low pre-treatment ADC and a greater decrease in PE in response to treatment were also associated with immune-activated tumor microenvironments as defined by RNA immune signatures. Breast MRI features hold promise as biomarkers of early immune response to treatment in HER2+ breast cancer.

Tandem mass tag (TMT) quantitative proteomics and phosphoproteomic of Takifugu rubripes infected with Cryptocaryon irritans

In this study, we identified the differentially expressed proteins in gills stimulated by infected ciliates and analyzed the immune mechanisms of T. rubripes infected with the ciliate Cryptocaryon irritans. Through liquid chromatography analysis, a total of 144 proteins were identified with significant differences, of which 58 were upregulated and 86 were downregulated. Among phosphorylated proteins, we identified a total of 167 significantly different phosphorylated proteins, of which 44 were upregulated, 123 were downregulated, 60 were upregulated, and 208 were downregulated. We analyzed the data of proteomics and Phosphorylated proteome quantification protein omics to finally identify three phosphorylated proteins (RPS27, eNOS and CaM) and two phosphorylated protein kinases(CaMKII and MAPK1) as potential biomarkers for T. rubripes immune responses. We finally identified three phosphorylated proteins (RPS27, eNOS and CaM) and two phosphorylated protein kinases (CaMKII and MAPK1) as potential biomarkers of immune response of T. rubripes. Our research findings provide new insights into the immune mechanism of T. rubripes, which may serve as an effective indicator of C. irritans infection in T. rubripes.

Elevated UTI Biomarkers in Symptomatic Patients with Urine Microbial Densities of 10,000 CFU/mL Indicate a Lower Threshold for Diagnosing UTIs.

The literature lacks consensus on the minimum microbial density required for diagnosing urinary tract infections (UTIs). This study categorized the microbial densities of urine specimens from symptomatic UTI patients aged ≥ 60 years and correlated them with detected levels of the immune response biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and interleukin-1-beta (IL-1β). The objective was to identify the microbial densities associated with significant elevation of these biomarkers in order to determine an optimal threshold for diagnosing symptomatic UTIs. Biobanked midstream voided urine samples were analyzed for microbial identification and quantification using standard urine culture (SUC) and multiplex-polymerase chain reaction (M-PCR) testing, while NGAL, IL-8, and IL-1β levels were measured via enzyme-linked immunosorbent assay (ELISA). NGAL, IL-8, and IL-1β levels were all significantly elevated at microbial densities ≥ 10,000 cells/mL when measured via M-PCR (p < 0.0069) or equivalent colony-forming units (CFUs)/mL via SUC (p < 0.0104) compared to samples with no detectable microbes. With both PCR and SUC, a consensus of two or more elevated biomarkers correlated well with microbial densities > 10,000 cells/mL or CFU/mL, respectively. The association between ≥10,000 cells and CFU per mL with elevated biomarkers in symptomatic patients suggests that this lower threshold may be more suitable than 100,000 CFU/mL for diagnosing UTIs.

Hemodialysis: The Life Boat for AKI Patients in the COVID Cytokine Storm.

Interleukin-6 (IL-6), a biomarker of hyperinflammatory immune response, can be used to determine the severity of coronavirus disease 2019 (COVID-19) in patients with multi-organ involvement requiring critical care. The aim of our study is to understand the utility of hemodialysis, not only in terms of reducing renal burden, but also improving the outcome by tackling the COVID cytokine storm syndrome. In this prospective, observational study, 126 patients admitted to the COVID intensive care unit (ICU) wards were treated with hemodialysis for acute kidney injury (AKI). Patients' routine baseline blood parameters were evaluated. IL-6 was measured predialysis in all patients and on the day of discharge in the patients who survived. Out of total 126 patients, 79 were survivors and 47 were nonsurvivors. Among nonsurvivors, majority were older (P = 0.009). Both the groups had a higher percentage of males (78.72% and 55.69% in survivors and nonsurvivors, respectively). Mean neutrophil lymphocyte ratio (NLR) and D-dimer level were significantly higher in nonsurvivors compared to survivors (P < 0.001). Mean serum urea, creatinine, and IL-6 levels were significantly greater in nonsurvivors (P < 0.001). Mean number of hemodialysis sessions received by survivors was higher. The curve between delta IL-6 and delta serum creatinine for survivors showed a significant positive association (r = 0.819, P < 0.001). Our study establishes IL-6 as a poor outcome predictor in COVID ICU patients with AKI. It also emphasizes the use of hemodialysis as a cost-effective lifesaving therapeutic interventional modality to not only improve the renal outcome, but also curb the cytokine storm by reducing IL-6 levels.

TIPS-18 TRIAL IN PROGRESS: A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2B STUDY TO ASSESS THE SAFETY AND EFFICACY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGONUCLEOTIDE (IMV-001) TARGETING IGF-1R, IN NEWLY DIAGNOSED PATIENTS WITH GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusioncriteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields (Optune®) prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.

Biomarkers for Immune Checkpoint Inhibitor Response in NSCLC: Current Developments and Applicability.

Lung cancer has the highest mortality rate among all cancer types, resulting in over 1.8 million deaths annually. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of non-small cell lung cancer (NSCLC). ICIs, predominantly monoclonal antibodies, modulate co-stimulatory and co-inhibitory signals crucial for maintaining immune tolerance. Despite significant therapeutic advancements in NSCLC, patients still face challenges such as disease progression, recurrence, and high mortality rates. Therefore, there is a need for predictive biomarkers that can guide lung cancer treatment strategies. Currently, programmed death-ligand 1 (PD-L1) expression is the only established biomarker for predicting ICI response. However, its accuracy and robustness are not consistently reliable. This review provides an overview of potential biomarkers currently under development or in the validation stage that hold promise in improving the classification of responders and non-responders to ICI therapy in the near future.

Biomarkers of immune checkpoint inhibitor response and toxicity: Challenges and opportunities.

Immune checkpoint inhibitors have transformed cancer therapy, but their optimal use is still constrained by lack of response and toxicity. Biomarkers of response may facilitate drug development by allowing appropriate therapy selection and focusing clinical trial enrollment. However, aside from PD-L1 staining in a subset of tumors and rarely mismatch repair deficiency, no biomarkers are routinely used in the clinic. In addition, severe toxicities may cause severe morbidity, therapy discontinuation, and even death. Here, we review the state of the field with a focus on our research in therapeutic biomarkers and toxicities from immune checkpoint inhibitors.

Biomarker Signatures of Severe Acute Kidney Injury in a Critically Ill Cohort of COVID-19 and Non-COVID-19 Acute Respiratory Illness.

We identified plasma biomarkers associated with severe acute kidney injury (AKI) during acute respiratory illness, and compared them to biomarkers associated with severe acute respiratory failure (ARF). Prospective observational cohort study enrolling March 2020 through May 2021, at three hospitals in a large academic health system. We analyzed 301 patients admitted to an ICU with acute respiratory illness. Outcomes were ascertained between ICU admission and day 14, and included: 1) severe AKI, defined as doubling of serum creatinine or new dialysis and 2) severe ARF, which included new or persistent need for high-flow oxygen or mechanical ventilation. We measured biomarkers of immune response and endothelial function, pathways related to adverse kidney and lung outcomes, in plasma collected within 24 hours of ICU admission. Severe AKI occurred in 48 (16%), severe ARF occurred in 147 (49%), and 40 (13%) patients experienced both. Two-fold higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR-1) (adjusted relative risk [aRR], 1.56; 95% CI, 1.24-1.96) and soluble triggering receptor on myeloid cells-1 (sTREM-1) (aRR, 1.85; 95% CI, 1.42-2.41), biomarkers of innate immune activation, were associated with higher risk for severe AKI after adjustment for age, sex, COVID-19, and Acute Physiology and Chronic Health Evaluation-III. These biomarkers were not significantly associated with severe ARF. Soluble programmed cell death receptor-1 (sPDL-1), a checkpoint pathway molecule, as well as soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), molecules involved with endothelial-vascular leukocyte adhesion, were associated with both severe AKI and ARF. sTNFR-1 and sTREM-1 were linked strongly to severe AKI during respiratory illness, while sPDL-1, sICAM-1 and sVCAM-1 were associated with both severe AKI and ARF. These biomarker signatures may shed light on pathophysiology of lung-kidney interactions, and inform precision medicine strategies for identifying patients at high risk for these organ injuries.

Impacts of replacing dietary fish meal with poultry by-product meal on growth, digestive enzymes and gut microbiota, biomarkers of metabolic and immune response, and resistance to Vibrio challenge in abalone (Haliotis discus hannai)

A 110-day feeding trial was carried out to investigate the impacts of replacing dietary fish meal (FM) with poultry by-product meal (PBM) on growth performance, digestion, gut microbiota, immunity, and disease resistance of abalone Haliotis discus hannai (initial weight: 22.53 ± 0.21 g). The control diet (PBM0) without PBM contained 20% of FM. Based on PBM0, the other four isonitrogenous (about 30% of crude protein) and isolipidic (about 4% of crude lipid) diets were formulated replacing 25, 50, 75 and 100% of FM by PBM (designated as PBM25, PBM50, PBM75 and PBM100), respectively. Every diet was fed to triplicate cages (40 × 35 × 70 cm) with 60 abalones per cage. At the end of the feeding trial, abalones were starved for 3 days and anesthetized with 5% ethanol before sampling. Results indicated that biomass gain of the abalone fed PBM75 (916.71 g) and PBM100 (659.93 g) was significantly lower than that of the abalone fed PBM0 (1222.51 g). Feed conversion ratio of the abalone fed PBM50 (2.93), PBM75 (2.89) and PBM100 (4.04) were significantly higher than that of the abalone fed PBM0 (2.37). The muscle crude protein content of the abalone fed PBM100 (16.01% wet weight) was significantly lower than that of the abalone fed PBM0 (16.67% wet weight). Activities of trypsin and α-amylase in the digestive gland in the PBM100 group (309.21 and 0.064 U/mg prot., respectively) were significantly lower than the PBM0 group (463.57 and 0.078 U/mg prot., respectively). When the substitution levels rose over 50%, expressions of phosphatidylinositol 3 kinase, threonine kinase/protein B, mammalian target of rapamycin and eukaryotic translation initiation factor 4E in muscle were significantly reduced, while 4E binding protein was significantly increased. The most abundant phyla across the abalones' gut were Proteobacteria and Firmicutes. Catalase (from 2.90 to 1.69 U/mL), superoxide dismutase (from 98.93 to 74.39 U/mL), lysozyme (from 345.86 to 247.81 U/mL) and acid phosphatase (from 21.68 to 15.71 U/100 mL) activities in cell-free hemolymph were markedly decreased with substitution level increasing. When the replacement levels rose over 50%, myeloid differentiation primary response gene 88 and tumor necrosis factor α expressions in the digestive gland were markedly upregulated, while β-defensin and mytimacin 6 expressions were markedly downregulated. The cumulative mortality of abalone challenged with Vibrio parahaemolyticus (1.0 × 107 CFU/mL) for 7 days was remarkably increased in the PBM50 (83.49%), PBM75 (89.56%) and PBM100 (100%) groups compared with the PBM0 group (58.82%). In conclusion, 50% of dietary FM could be replaced by PBM without influencing abalone growth. When the replacement level was over 50%, the growth and immunity of abalone were decreased, and the mTOR pathway was negatively affected.

CCL5 might be a prognostic biomarker and associated with immuno-therapeutic efficacy in cancers: A pan-cancer analysis

PurposeChemokine ligand 5 (CCL5), a vital member of the CC chemokine family, plays diverse roles in tumorigenesis, metastasis, and prognosis in various human tumors. However, no pan-cancer analysis has been conducted to illustrate its distinctive effects on clinical prognosis via underlying mechanisms and biological characteristics. MethodsHerein, we exploited the existed public bioinformatics database, primarily TCGA database and GTEx data, to comprehensively analyze the value of CCL5 involved in patient prognosis. ResultsThis study found that CCL5 was excessively expressed in most tumors and significantly associated with clinical prognosis in 10 out of 33 types of tumors. Notably, CCL5 might be an independent predictive biomarker of clinical outcome in SKCM patients, confirmed by univariate and multivariate Cox regression analysis. Furthermore, we acquired the genetic alteration status of CCL5 in multiple types of tumor tissues from TCGA cohorts. We revealed a potential correlation between the expression level of CCL5 and tumor mutational burden in 33 types of tumors. In addition, data showed that DNA methylation was associated with CCL5 gene expression in THCA, PRAD, LUSC, and BRCA cancers. Immune infiltration and immune checkpoints are fine indexes for evaluating immunotherapy. We uncovered that CCL5 was negatively correlated with the immune infiltration of CD8+ T cell, CD4+ T cell, macrophages, and gamma delta T cells in BRCA-basal and CESC tumors, while a significant positive correlation was observed in BLCA, COAD and other 7 types of tumors. Besides, CCL5 was closely associated with the immune checkpoint molecules in 8 types of tumors. The TIDE score was less in the CCL5 high-expressed group than in the CCL5 low-expressed group in SKCM patients, which indicated that CCL5 might be a fine monitor of immune response for immunotherapy. GO enrichment analysis data uncovered that cytokine-cytokine receptor interaction and chemokine signaling might be involved in the role of CCL5 in regulating tumor pathogenesis and prognosis. ConclusionIn conclusion, CCL5 was preliminarly identified as a biomarker of immune response and prognosis for tumors patients via our first comprehensive pan-cancer analysis.

Tissue Resistance Decrease during Irreversible Electroporation of Pancreatic Cancer as a Biomarker for the Adaptive Immune Response and Survival

PurposeTo correlate irreversible electroporation (IRE) procedural resistance changes with survival outcomes and the IRE-induced systemic immune response in patients with locally advanced pancreatic cancer (LAPC). Materials and MethodsData on IRE procedural tissue resistance (R) features and survival outcomes were collected from patients with LAPC treated within the context of 2 prospective clinical trials in a single tertiary center. Preprocedural and postprocedural peripheral blood samples were prospectively collected for immune monitoring. The change (ie, decrease) in R during the first 10 test pulses (ΔR10p) and during the total procedure (ΔRtotal) were calculated. Patients were divided in 2 groups on the basis of the median change in R (large ΔR vs small ΔR) and compared for differences in overall survival (OS) and progression-free survival and immune cell subsets. ResultsA total of 54 patients were included; of these, 20 underwent immune monitoring. Linear regression modeling showed that the first 10 test pulses reflected the change in tissue resistance during the total procedure appropriately (P < .001; R2 = 0.91). A large change in tissue resistance significantly correlated with a better OS (P = .026) and longer time to disease progression (P = .045). Furthermore, a large change in tissue resistance was associated with CD8+ T cell activation through significant upregulation of Ki-67+ (P = .02) and PD-1+ (P = .047). Additionally, this subgroup demonstrated significantly increased expression of CD80 on conventional dendritic cells (cDC1; P = .027) and PD-L1 on immunosuppressive myeloid-derived suppressor cells (P = .039). ConclusionsIRE procedural resistance changes may serve as a biomarker for survival and IRE-induced systemic CD8+ T cell and cDC1 activation.

Efficacy of Immune Checkpoint Blockade and Biomarkers of Response in Lymphoma: A Narrative Review.

Immune checkpoint blockade (ICB) has revolutionized the prognosis of several advanced-stage solid tumors. However, its success has been far more limited in hematological malignancies and is mostly restricted to classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBCL). In patients with non-Hodgkin lymphoma (NHL), response to PD-1/PD-L1 ICB monotherapy has been relatively limited, although some subtypes are more sensitive than others. Numerous predictive biomarkers have been investigated in solid malignancies, such as PD-L1 expression, tumor mutational burden (TMB) and microsatellite instability (MSI), among others. This review aims to appraise the current knowledge on PD-1/PD-L1 ICB efficacy in lymphoma when used either as monotherapy or combined with other agents, and describes potential biomarkers of response in this specific setting.

#3372 HOST RESPONSE CHANGES ASSOCIATED WITH PERSISTENT ACUTE KIDNEY INJURY IN CRITICALLY ILL PATIENTS WITH COVID-19

Abstract Background and Aims In sepsis, the dysregulated host response has been, at least in part, linked to development of acute kidney injury (AKI) and its duration. Data on the host response to COVID-19 and development of persistent-AKI (duration &amp;gt; 48 h) in critically ill patients are scarce. We hypothesized that COVID-19 infected patients who develop persistent-AKI have different host response aberrations. To address this hypothesis, we sequentially measured host immune response biomarkers in critically ill patients admitted to the intensive care unit (ICU). Method We included patients admitted to the ICU from two tertiary hospitals and one primary care hospital between March and July 2020 (first wave). All patients had PCR-confirmed COVID-19. Excluded were readmitted patients, transfers from another ICU, and patients with chronic kidney disease (CKD stage 3 or higher). The presence of AKI was assessed by using hourly urine output and daily serum creatinine levels, and classified into 3 stages according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In a subset of patients admitted to the two tertiary hospitals (n=113), 41 plasma protein biomarkers were sequentially measured using a Luminex platform or ELISA, and categorized into five pathophysiological domains: systemic inflammation, endothelial cell activation and dysfunction, coagulation activation, kidney dysfunction, and lung dysfunction. Mixed effects models were used to analyse longitudinal data. Results Of 185 ICU admissions enrolled, 8 were excluded because of existing CKD. Of the remaining 177 patients, 106 patients (59.9%) had AKI within the first 48 h of admission; of these, 76 patients (71.7%) had persistent AKI and 30 patients (28.3%) transient AKI. Patients with persistent AKI more often were obese and had a history of hypertension. A higher disease severity – as determined by the sequential organ failure assessment (SOFA) score - was observed in the persistent AKI group, which was driven by the renal component as the non-renal SOFA score was similar between no-AKI, transient-, and persistent AKI. Sequential protein biomarker analyses revealed that five biomarkers were significantly elevated in persistent-AKI compared to transient-AKI in the first four days, mainly related to inflammation (triggering receptor expressed on myeloid cells-1 [TREM-1], p=.003; tumour necrosis factor receptor 1 [TNF-RI], p &amp;lt; 0.001); lung dysfunction (clara cell secretory protein [CC16], p &amp;lt; 0.001), and kidney dysfunction (Cystatin C [p &amp;lt; 0.001]; neutrophil gelatinase-associated lipocalin [NGAL], p &amp;lt; 0.001). Plasma protein biomarkers reflective of endothelial cell- and coagulation activation were not different in patients with persistent-AKI as compared to patients with transient-AKI. No differences in plasma biomarkers were observed between transient AKI and no-AKI. Conclusion Transient AKI and no-AKI revealed little to no differences, while the persistent AKI group demonstrated stronger host response anomalies across the pathophysiological domains of inflammation and lung dysfunction. In contrast to what has been observed in non-COVID-19-related sepsis, endothelial injury and coagulation activation markers were not associated with AKI trajectories. These findings suggest that COVID-19 can induce a robust immune response that contributes to persistence of AKI, largely mediated through inflammatory responses.

Sex-Specific Effects of Body Composition on Tumor Microenvironment in Non–Small Cell Lung Cancer

BackgroundThere exists a gap in understanding the interaction between sex and obesity on tumor microenvironment in non–small cell lung cancer (NSCLC). We demonstrate the combined effects of sex and body composition on clinically relevant biomarkers of NSCLC immune response. MethodsA cohort of 409 patients with NSCLC was subdivided into 4 groups jointly defined by body mass index (BMI; cutoff of 25 kg/m2) and sex (male–high BMI, male–low BMI, female–high BMI, female–low BMI). Associations between these sex-BMI groups and tumor inflammation (expression of 161 immune response genes), cell proliferation (expression of 10 cell proliferation genes), and programmed cell death ligand 1 (PD-L1; through immunohistochemistry and targeted RNA sequencing) were assessed by Kruskal-Wallis and Wilcoxon rank sum tests for overall and pairwise tests, respectively. ResultsWe observed an overall significant association of sex-BMI with tumor inflammation (P < .001) and cell proliferation (P = .002). On pairwise analysis, high-BMI females had significantly higher tumor inflammation compared with low-BMI females (P = .002). In addition, women with a high (P = .004) and low (P = .008) BMI had significantly higher tumor inflammation compared with men with a high and low BMI, respectively. Low-BMI females (P = .01) and males (P = .01) had more cell proliferation. PD-L1 expression by RNA sequencing (P = .001) but not by immunohistochemical analysis differed significantly with sex-BMI. High-BMI females had significantly higher PD-L1 expression compared with low-BMI females (P = .01). ConclusionsWe demonstrate that tumor inflammation and PD-L1 expression are more strongly associated with BMI in women than in men. Additional studies are required to better understand the mechanisms underlying these effects and their role in response to checkpoint inhibitors in NSCLC.

Prospective evaluation of pathologic response with neoadjuvant chemo-immunotherapy in metaplastic breast cancer.

606 Background: Metaplastic breast cancer (MpBC) is a rare aggressive histologic type of breast cancer that is often resistant to standard chemotherapy with pathologic complete response (pCR) rates ranging between 2-23%. PDL1 expression has been reported in up to 95% of primary MpBCs suggesting that response rates may be improved with addition of immune checkpoint blockade (ICB). Here we evaluate pCR rates (ypT0/is ypN0) in stage I-III MpBCs receiving neoadjuvant chemo-immunotherapy (NAT). Methods: The Memorial Sloan Kettering Cancer Center Rare Breast Cancer Program (CARE-4-RARE) is a new clinical and translational program dedicated to the study of rare breast cancers. Since the start of the program, 15 patients (pts) with early-stage MpBC have completed treatment with the neoadjuvant KEYNOTE-522 regimen. Wilcoxon rank-sum and Fisher’s exact tests were used to compare characteristics according to pCR status. All statistical tests used a significance level of 5%. Results: Median age at diagnosis was 50 (range, 43-60). All pts were female, 13% self-identified as Asians, 33% as Black and 53% as White. All tumors were poorly differentiated and of triple-negative phenotype, median tumor size was 3.2cm, 80% had stage II disease and 20% were clinically node positive. Metaplastic subtypes included 5 matrix-producing (33%), 3 spindle (20%), 4 squamous (27%), 3 mixed (20%). Of the 15 pts, 4 (27%) achieved a pCR, which suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy. We did not observe a significant difference in clinicopathological features between pCR vs. non-pCR groups. We observed numerical differences in pCR between MpBC subtypes though the p-value was not significant due to limited sample size. Of these 4 pts, 2 had matrix-producing and 2 had mixed subtypes. Two pts with pCR only received Cb+P+Pem. Three pts (20%) experienced PD (squamous n = 2, spindle n = 1) necessitating discontinuation of NAT and expediting surgery. Conclusions: This is the first prospective study to evaluate neoadjuvant ICB in MpBC. These data suggest the possibility of a higher than expected pCR rate in MpBC with the addition of ICB to chemotherapy (27%). This work suggests that neoadjuvant ICB should be considered in MpBC with close monitoring. Notably, 50% of reported pCR in this cohort were in pts who only received Cb+P+Pem. In spite of improved pCR rates, 20% of pts progressed during NAT highlighting the need for better treatment strategies in this treatment-refractory subset of MpBC and close monitoring to allow resection before progression to inoperability. The dichotomy in responses to ICB (super-responsive vs. super-refractory) may suggest the presence of unique biomarkers for immune response in MpBC. By the 2023 ASCO Annual Meeting a total of 26 pts will have completed NAT; we will report updated outcomes along with correlative immune biomarkers (sTIL, PDL1, TMB).