First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes: an exploratory analysis of immune biomarkers.

BACKGROUND: IMCY-0098, a synthetic peptide developed to halt disease progression via elimination of key immune cells in the autoimmune cascade, has shown a promising safety profile for the treatment of type 1 diabetes (T1D) in a recent phase 1b trial. This exploratory analysis of data from that trial aimed to identify the patient biomarkers at baseline associated with a positive response to treatment and examined the associations between immune response parameters and clinical efficacy endpoints (as surrogates for mechanism of action endpoints) using an artificial intelligence-based approach of unsupervised explainable machine learning. METHODS: We conducted an exploratory analysis of data from a phase 1b, dose-escalation, randomized, placebo-controlled study of IMCY-0098 in patients with recent-onset T1D. Here, a panel of markers of T cell activation, memory T cells, and effector T cell response were analyzed via descriptive statistics. Artificial intelligence-based analyses of associations between all variables, including immune responses and clinical responses, were performed using the Knowledge Extraction and Management (KEM®) v 3.6.2 analytical platform. RESULTS: The relationship between all available patient data was investigated using unsupervised machine learning implemented in the KEM® environment. Of 15 associations found for the dose C group (450 µg subcutaneously followed by 3 × 225 µg subcutaneously), seven involved human leukocyte antigen (HLA) type, all of which identified improvement/absence of worsening of disease parameters in DR4+ patients and worsening/absence of improvement in DR4- patients. This association with DR4+ and non-DR3 was confirmed using the endpoints normalized area under the curve C-peptide from mixed meal tolerance tests where presence of DR4 HLA haplotype was associated with an improvement in both endpoints. Exploratory immune analysis showed that IMCY-0098 dose B (150 µg subcutaneously followed by 3 × 75 µg subcutaneously) and dose C led to an increase in presumed/potentially protective antigen-specific cytolytic CD4+ T cells and a decrease in pathogenic CD8+ T cells, consistent with the expected mechanism of action of IMCY-0098. The analysis identified significant associations between immune and clinical responses to IMCY-0098. CONCLUSIONS: Promising preliminary efficacy results support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D. TRIAL REGISTRATION: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27.

Serum immune biomarker levels combined with hepatitis B virus infection status predict early recurrence of early-stage hepatocellular carcinoma with microvascular invasion after liver resection.

INTRODUCTION: The tumor immune response plays a vital role in cancer recurrence in patients with malignancies. We aim to clarify the risk factors for early recurrence and investigate the efficacy of blood-based biomarkers to predict the risk of early recurrence in early-stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy. MATERIALS AND METHODS: A total of 101 cases of HCC with MVI who underwent liver resection were enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of early recurrence. We calculated the area under the receiver operating characteristic curve to evaluate the performance of the four biomarkers identified as risk factors for early recurrence. RESULTS: Multiple logistic regression analysis indicated that complement (C)4, cluster of differentiation (CD)4+, immunoglobulin A (IgA), and hepatitis B virus (HBV) DNA of greater than 500 IU/mL were correlated with early recurrence of HCC. The area under the curve was greater for the combination model than for the HBV DNA, CD4+, IgA, or C4 models alone. CONCLUSION: Preoperative serum CD4+, C4, IgA, and HBV DNA levels were linked with early recurrence of early-stage HCC with MVI and the combination model was of considerable predictive value for the prognosis of HCC with MVI.

Prognostic value of preoperative soluble interleukin 2 receptor α as a novel immune biomarker in epithelial ovarian cancer.

PURPOSE: Epithelial ovarian cancer (EOC) is regarded as the deadliest gynecological cancer, and the demand for novel noninvasive prognostic biomarkers remains significant. This study aimed to investigate the prognostic value of preoperative blood biomarkers in EOC patients. METHODS: In total, 73 patients who had undergone ovarian mass resection were enrolled. Serum concentration of biomarkers, including soluble interleukin 2 receptor α (sIL-2R), was measured 1-2 weeks before surgery. Independent prognostic factors for progression-free survival (PFS) were investigated with multivariate Cox regression analysis. A prognostic model was subsequently developed and evaluated by discrimination, calibration and clinical net benefit. Furthermore, transcriptome data of 376 EOC cases from The Cancer Genome Atlas (TCGA) were analyzed with ESTIMATE, CIBERSORT and Maftools algorithm to evaluate the correlation of IL2RA expression with tumor immune microenvironment and immunotherapeutic response. RESULTS: High sIL-2R concentration was found to be the only significant prognostic blood biomarker for PFS by multivariate Cox regression analysis in our center. A prognostic nomogram was developed with satisfactory discrimination, calibration and clinical net benefit. In addition, higher IL2RA expression was significantly associated with higher immune scores, activated CD4+ T cells, M2 macrophages and resting dendritic cells in TCGA data. Furthermore, IL2RA expression was closely related to TMB scores. CONCLUSIONS: sIL-2R is a potential prognostic immune biomarker for EOC patients, and a comprehensive prognostic model comprising sIL-2R with satisfactory discrimination and clinical appliance was developed. Therefore, we recommend routine sIL-2R testing in EOC patients.

Dynamic changes in maternal immune biomarkers during labor in nulliparous vs multiparous women.

BACKGROUND: Immunomodulation is observed in human parturition. However, data from longitudinal studies for the prelabor phase and the active phase of labor are lacking, and no study had compared the immune responses during labor between nulliparous and multiparous women. OBJECTIVE: This study aimed to investigate the temporal changes of immune biomarkers in maternal blood from the prelabor phase to the latent and active phases of labor and to compare the dynamic changes between nulliparous and multiparous women. STUDY DESIGN: A prospective case-control study was conducted on women who had induction of labor at term followed by vaginal delivery. Maternal blood was serially collected at 3 consecutive time points: (1) before the onset of labor, (2) during the latent phase of labor, and (3) during the active phase of labor. Peripheral immune cells were measured by 4-color flow cytometry, and the plasma concentrations of cytokines and chemokines were measured by cytometric bead arrays. A longitudinal comparison was made to assess the dynamic changes in inflammatory parameters over 3 time points in nulliparous and multiparous women, respectively, and a cross-sectional comparison was made between nulliparous and multiparous women. RESULTS: A total of 40 women, including 20 nulliparous and 20 multiparous, were included in the study. Prelabor circulating levels of macrophage inflammatory protein-1ß, monokine induced by gamma interferon, and interferon gamma-induced protein-10 were higher in multiparous women than in nulliparous women. In the latent phase of labor, the innate immune system in both groups responded with increases in neutrophils and interleukin 6, and the nulliparous women showed a more pronounced response. During the active phase of labor, such innate immune response continued with both groups, with additional increases in natural killer cells, monocyte chemoattractant protein-1, interleukin 8, and interleukin 10. Conversely, the adaptive immune system in nulliparous women showed a reduction in both cytotoxic and helper T cells, whereas the adaptive immune system in multiparous women only had a reduction in helper T cells, showing a smaller reduction. CONCLUSION: Innate and adaptive immune responses partake in immunomodulation during human parturition. Nulliparous and multiparous women showed different responses in their blood levels of immune cells and biomarkers during the different phases of labor.

Immune Oncology Biomarkers in Lung Cancer: an Overview.

PURPOSE OF REVIEW: Lung cancer is still the first cause of cancer-related deaths worldwide. The development of immune checkpoint inhibitors (ICI) has drastically changed the prognosis of some patients, but the rate of long responders does not exceed 20%. Moreover, ICIs are not adverse events-free and remain expensive. Therefore, predictive biomarkers of long-term benefit to ICI are required. RECENT FINDINGS: The two main fields being evaluated currently are PD-L1 expression and tumor mutational burden (TMB). The first one is the only one used in routine practice, and the second is being evaluated in phase 3 clinical trials. In addition, other biomarkers are being assessed as complex signatures, tumor-infiltrated lymphocytes, T cell receptor repertoire, or molecular profiling. The aim of this review is to summarize the current validated or promising biomarkers in lung cancer which could help to better select patients who will respond to ICI.

EBV and vitamin D status in relapsing-remitting multiple sclerosis patients with a unique cytokine signature.

Multiple sclerosis, a debilitating autoimmune and inflammatory disease of the central nervous system, is associated with both infectious and non-infectious factors. We investigated the role of EBV infection, vitamin D level, and cytokine signature in MS patients. Molecular and serological assays were used to investigate immune biomarkers, vitamin D level, and EBV status in 83 patients with relapsing-remitting multiple sclerosis and 62 healthy controls. In total, 98.8 % of MS patients showed a history of EBV exposure compared to 88.6 % in the healthy group (p = 0.005). EBV DNA load was significantly higher in MS patients than healthy subjects (p < 0.0001). Using a panel of biomarkers, we found a distinct transcriptional signature in MS patients compared to the healthy group with mRNA levels of CD73, IL-6, IL-23, IFN-γ, TNF-α, IL-15, IL-28, and IL-17 significantly elevated in MS patients (p < 0.0001). In contrast, the mRNA levels for TGF-ß, IDO, S1PR1, IL-10, and CCL-3 were significantly lower in MS patients compared to healthy controls (p < 0.0001). No significant differences were found with the mRNA levels of IL-13, CCL-5, and FOXP3. Interestingly, in MS patients we found an inverse correlation between vitamin D concentration and EBV load, but not EBNA-1 IgG antibody levels. Our data highlight biomarker correlates in MS patients together with a complex interplay between EBV replication and vitamin D levels.

Serum Interleukin-34 Levels Are Elevated in Patients with Systemic Lupus Erythematosus.

Interleukin-34 (IL-34) was initially identified as an alternative ligand for the colony-stimulating factor-1 receptor (CSF-1R) to mediate the biology of mononuclear phagocytic cells. Recently, IL-34 was found to be associated with chronic inflammation, such as in rheumatoid arthritis (RA). Both RA and systemic lupus erythematosus (SLE) are multifactorial autoimmune diseases and are characterized by excessive immune and inflammatory responses. Thus, we investigated whether IL-34 is involved in the pathogenesis of SLE. In all, 78 SLE patients and 53 healthy controls were enrolled in the research. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the concentrations of serological IL-34. Then serum IL-34 levels between the SLE group and healthy controls were analyzed by the Mann-Whitney U test. Meanwhile, the correlations between the serum IL-34 levels and disease activity indexes and other established serum markers were assessed. Furthermore, the serum IL-34 levels of 20 active SLE patients were reevaluated when diseases were in the remission stage from corticosteroids or immunosuppressive drugs. Serum IL-34 levels were significantly higher in SLE patients compared to healthy controls. Their levels were remarkably associated with accumulation of the clinical features of SLE. Additionally, IL-34 titers were positively correlated with the SLE disease activity indexes, anti-double-stranded DNA antibody (anti-dsDNA) titers and C-reactive protein (CRP) levels, and inversely with complement3 (C3) levels. Moreover, serum IL-34 levels were significantly decreased after successful treatment of SLE. Serum IL-34 could be a candidate biomarker for SLE as there are elevated serum levels in treatment-naive SLE patients and we saw a significant decrease after effective treatment.

The war between the immune system and the tumor - using immune biomarkers as tracers.

Nowadays, immunotherapy is one of the most promising anti-tumor therapeutic strategy. Specifically, immune-related targets can be used to predict the efficacy and side effects of immunotherapy and monitor the tumor immune response. In the past few decades, increasing numbers of novel immune biomarkers have been found to participate in certain links of the tumor immunity to contribute to the formation of immunosuppression and have entered clinical trials. Here, we systematically reviewed the oncogenesis and progression of cancer in the view of anti-tumor immunity, particularly in terms of tumor antigen expression (related to tumor immunogenicity) and tumor innate immunity to complement the cancer-immune cycle. From the perspective of integrated management of chronic cancer, we also appraised emerging factors affecting tumor immunity (including metabolic, microbial, and exercise-related markers). We finally summarized the clinical studies and applications based on immune biomarkers. Overall, immune biomarkers participate in promoting the development of more precise and individualized immunotherapy by predicting, monitoring, and regulating tumor immune response. Therefore, targeting immune biomarkers may lead to the development of innovative clinical applications.

High Level of CD8+PD-1+ Cells in Patients with Chronic Myeloid Leukemia Who Experienced Loss of MMR after Imatinib Discontinuation.

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.

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.

The effects of metabolic indicators and immune biomarkers on pregnancy outcomes in women with recurrent spontaneous abortion: a retrospective study.

Background: The etiology of recurrent spontaneous abortion (RSA) remains elusive despite specific investigations affirming the association between RSA and thyroid autoimmunity (TAI). This study explores the immunological and metabolic profiles of RSA patients exhibiting positive thyroid antibodies and their connection with the rates of first-trimester miscarriage and live births. The aim is to provide further guidance for clinical interventions. Methods: A retrospective analysis included 478 women with RSA. Thyroid profile, thyroid peroxidase antibodies, and anti-thyroglobulin antibodies were measured in all participants. The clinical characteristics and pregnancy outcomes of RSA women were compared between thyroid autoimmunity (TAI)-positive and TAI-negative patients. Significant factors associated with adverse pregnancy outcomes and risk prediction models were explored in TAI-positive patients. Correlation analysis was used to identify specific metabolic or immune biomarkers associated with thyroid autoantibodies. Results: The prevalence of TAI was 18.6%. Compared with women without TAI, the thyroid-stimulating hormone (TSH) concentration of TAI-positive RSA was significantly higher (2.80 ± 2.98 vs 1.89 ± 1.17, p=0.006). After 28 weeks, the live birth rate of the TAI-positive group was lower than that of the TAI-negative group, with statistical significance (p<0.05). The immune biomarkers that differed between RSA women with live births and those with first-trimester miscarriages were complement C4 and interleukin-6, respectively, in TAI-negative and TAI-positive women. Then, a risk prediction model for first-trimester miscarriage was constructed for TAI-positive women with an AUC of 0.81. Finally, some factors related to thyroid peroxidase antibody (TPO-Ab) levels were explored, and it was found that TPO-Ab levels were positively correlated with free thyroxine and negatively correlated with 25 hydroxyvitamin D, interleukin-4, and fasting blood glucose in RSA patients. Conclusion: TAI-positive RSA patients have higher first-trimester miscarriage rates and a lower live birth rate, which may be related to metabolic immune shifts in TAI-positive RSA patients.

Dynamic evaluation of blood immune cells predictive of response to immune checkpoint inhibitors in NSCLC by multicolor spectrum flow cytometry.

Introduction: Immune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients. Methods: PBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis. Results: Our findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5-42, P=0.01]. A higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2-55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14+HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively. Conclusion: Our preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation.

Gastric Cancer: Molecular Mechanisms, Novel Targets, and Immunotherapies: From Bench to Clinical Therapeutics.

Gastric cancer is a global health concern, ranking fifth in cancer diagnoses and fourth in cancer-related deaths worldwide. Despite recent advancements in diagnosis, most cases are detected at advanced stages, resulting in poor outcomes. However, recent breakthroughs in genome analysis have identified biomarkers that hold positive clinical significance for GC treatment. These biomarkers and classifications offer the potential for more precise diagnostic and therapeutic approaches for GC patients. In this review, we explore the classification and molecular pathways in this disease, highlighting potential biomarkers that have emerged in recent studies including targeted therapies and immunotherapies. These advancements provide a promising direction for improving the management of GC.

A pilot study on some critical immune elements in HBV infection: evidence of Alpha-1 Antitrypsin as an immunological biomarker.

Aim: This study is an attempt to screen the key immune elements that participate during HBV infection and the related pathways that are modulated. Background: The pathogenesis of Hepatitis B virus and the corresponding clinical manifestations in the host are primarily immune-mediated. Methods: This study utilizes a PCR array to screen immune-related genes that are differentially expressed in the presence of the virus in HBV replicating HepG2.2.15 cells as compared to control HepG2 cells. The significantly up-regulated genes were subjected to bioinformatic analysis utilizing GSEA and STRING. Additionally, ELISA was used to corroborate the levels of Alpha 1 antitrypsin (AAT) from patients' sera. Results: The expressions of 31% of the studied genes were significantly up-regulated (> 2-fold, p<0.05) in HepG2.2.15 cells compared to controls, and this included the SERPINA1, FN1, IL1R2, LBP, LY96, LYZ and PROC genes. When they were clustered based on biological processes, signaling pathways, and disease progression, the genes related to biotic stimulus, complement-coagulation cascades, and fibrosis, respectively, showed the highest (p<0.05) enrichment. Analysis of patients' sera by ELISA revealed that the serum AAT (SERPINA1) levels were significantly higher in asymptomatic carriers and in patients with chronic liver disease than in controls (p<0.05). Moreover, SERPINA1 levels were also positively correlated with the levels of serum ALT (r=0.4495, p<0.05) among HBV infected patients. Conclusion: The current study highlights the key immune elements and pathways that are modulated during HBV infection and proposes the possible use of AAT as a non-invasive immunological biomarker to follow the progression of liver disease.

The prognostic value of a 4-factor neoimmunologic score system in non-small cell lung cancer.

The role of distinct immune cell types in modulating cancer progression has recently gained attention. The immune context is indicated by the abundance of immune infiltration based on quantified lymphocytes in the core of tumors (CT) and invasive tumor margin (IM). Novel immune biomarkers could potentially complement tumor-node-metastasis (TNM) classification for non-small cell lung cancers (NSCLCs), thereby improving prognostic accuracy. This study evaluated the prognostic value of a newly established immunologic score (neo-IS) in patients with NSCLC. We detected 10 immune biomarkers, including CD45RO, CD3, CD8, CD68, CD163, CD66b, FoxP3, PD-1, PD-L1, and TIM-3, in 350 patients with NSCLC from 2 cohorts using immunohistochemistry (IHC). The 3- and 5-year survival and overall survival (OS) rates were evaluated. An immunologic prediction model specifically for NSCLC patients, the neo-immunologic score (neo-ISNSCLC ), was constructed using a Cox proportional hazards regression model. In the discovery cohort (n = 250), the establishment of neo-ISNSCLC was based on 4 immune biomarkers: CD3+IM , CD8+CT , FoxP3+IM , and PD-1+IM . Significant prognostic differences were found upon comparing low-ISNSCLC patients and high-ISNSCLC patients. The OS rate in the high-ISNSCLC group was significantly longer than that in the low-ISNSCLC group (67.5 months vs. 51.2 months, p < 0.001). The neo-ISNSCLC was validated in the validation cohort (n = 100), and the results were confirmed. Multivariate analyses indicated that neo-ISNSCLC was an independent indicator of prognosis in patients with NSCLC. Finally, we combined neo-ISNSCLC with clinicopathologic factors to establish a tumor-node-metastasis-immune (TNM-I) staging system for clinical use, which showed better prediction accuracy than the TNM stage.

Peripheral Blood Transcriptome in Breast Cancer Patients as a Source of Less Invasive Immune Biomarkers for Personalized Medicine, and Implications for Triple Negative Breast Cancer.

Transcriptome studies of peripheral blood cells can advance our understanding of the systemic immune response to the presence of cancer and the mechanisms underlying cancer onset and progression. This enables the identification of novel minimally invasive immune biomarkers for early cancer detection and personalized cancer management and may bring forward new immunotherapy options. Recent blood gene expression analyses in breast cancer (BC) identified distinct patient subtypes that differed in the immune reaction to cancer and were distinct from the clinical BC subtypes, which are categorized based on expression of specific receptors on tumor cells. Introducing new BC subtypes based on peripheral blood gene expression profiles may be appropriate, since it may assist in BC prognosis, the identification of patients likely to benefit from immunotherapy, and treatment efficacy monitoring. Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous, and difficult-to-treat disease, and identification of novel biomarkers for this BC is crucial for clinical decision-making. A few studies have reported TNBC-enriched blood transcriptional signatures, mostly related to strong inflammation and augmentation of altered immune signaling, that can differentiate TNBC from other classical BC subtypes and facilitate diagnosis. Future research is geared toward transitioning from expression signatures in unfractionated blood cells to those in immune cell subpopulations.

TOX as a potential target for immunotherapy in lymphocytic malignancies.

TOX (thymocyte selection-associated HMG BOX) is a member of a family of transcriptional factors that contain the highly conserved high mobility group box (HMG-box) region. Increasing studies have shown that TOX is involved in maintaining tumors and promoting T cell exhaustion. In this review, we summarized the biological functions of TOX and its contribution as related to lymphocytic malignancies. We also discussed the potential role of TOX as an immune biomarker and target in immunotherapy for hematological malignancies.

Immune Infiltrates in Breast Cancer: Recent Updates and Clinical Implications.

In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC prognosis and response to treatment. Indeed, the evaluation of TILs on primary tumors proved to be strongly prognostic in triple-negative (TN) BC patients treated with either adjuvant or neoadjuvant chemotherapy, as well as in early TNBC patients not receiving any systemic treatment, thus gaining level-1b evidence in this setting. In addition, a strong relationship between TILs and pathologic complete response after neoadjuvant chemotherapy has been reported in all BC subtypes and the prognostic role of higher TILs in early HER2-positive breast cancer patients has also been demonstrated. The interest in BC immune infiltrates has been further fueled by the introduction of the first immune checkpoint inhibitors in the treatment armamentarium of advanced TNBC in patients with PD-L1-positive status by FDA-approved assays. However, despite these advances, a biomarker capable of reliably and exhaustively predicting immunotherapy benefit in BC is still lacking, highlighting the imperative need to further deepen this issue. Finally, more comprehensive evaluation of immune infiltrates integrating both the quantity and quality of tumor-infiltrating immune cells and incorporation of TILs in composite scores encompassing other clinically or biologically relevant biomarkers, as well as the adoption of software-based and/or machine learning platforms for a more comprehensive characterization of BC immune infiltrates, are emerging as promising strategies potentially capable of optimizing patient selection and stratification in the research field. In the present review, we summarize available evidence and recent updates on immune infiltrates in BC, focusing on current clinical applications, potential clinical implications and major unresolved issues.

A prognostic immune predictor, HLA-DRA, plays diverse roles in non-muscle invasive and muscle invasive bladder cancer.

BACKGROUND: There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). MATERIALS AND METHODS: Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa. RESULTS: Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers. CONCLUSIONS: High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology.

Potential Immune Biomarker Candidates and Immune Subtypes of Lung Adenocarcinoma for Developing mRNA Vaccines.

mRNA vaccines against cancer have advantages in safety, improved therapeutic efficacy, and large-scale production. Therefore, our purpose is to identify immune biomarkers and to analyze immune status for developing mRNA vaccines and selecting appropriate patients for vaccination. We downloaded clinical information and RNA-seq data of 494 LUAD patients from TCGA. LUAD mutational information was hierarchically clustered by NMF package (Version 0.23.0). DeconstructSigs package (Version 1.8.0) and NMF consistency clustering were used to identify mutation signatures. Maftools package (Version 2.6.05) was used to select LUAD-related immune biomarkers. TIMER was used to discuss the correlation between genetic mutations and cellular components. Unsupervised clustering Pam method was used to identify LUAD immune subtypes. Log-rank test and univariate/multivariate cox regression were used to predict the prognosis of immune subtypes. Dimensionality reduction analysis was dedicated to the description of LUAD immune landscape. LUAD patients are classified into four signatures: T >C, APOBEC mutation, age, and tobacco. Then, GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Next, we clustered five LUAD-related immune subtypes (IS1-IS5) by prognostic prediction. IS3 showed prolonged survival. The reliability of our five immune subtypes was validated by Thorsson's results. IS2 and IS4 patients had high tumor mutation burden and large number of somatic mutations. Besides, we identified that immune subtypes of cold immunity (patients with IS2 and IS4) are ideal mRNA vaccination recipients. Finally, LUAD immune landscape revealed immune cells and prognostic conditions, which provides important information to select patients for vaccination. GPRIN1, MYRF, PLXNB2, SLC9A4, TRIM29, UBA6, and XDH are potential LUAD-related immune biomarker candidates to activate the immune response. Patients with IS2 and IS4 might potentially be immunization-sensitive patients for vaccination.