Immune Response In Patients Research Articles

Investigation into the immune microenvironment of gastroenteropancreatic high-grade neuroendocrine carcinoma.

e16244 Background: Gastroenteropancreatic high-grade neuroendocrine carcinomas (GEP HG-NEC) are aggressive cancers with poor survival and limited therapies. Using high-throughput gene expression analysis, we report the tumor-immune system interactions within the tumor microenvironment (TME), differentially expressed genes based on age, tumor location, survival, and objective response rate (ORR) to systemic therapy with the aim to drive future effective therapy research. Methods: We evaluated patients diagnosed with GEP HG-NEC from 2010-2021 for a pilot study and included those with adequate tumor samples. RNA was analyzed using the NanoString nCounter PanCancer IO 360 panel. Logistic regression modeling was used for hypothesis testing associated with best overall response. Cox model was used for testing overall survival (OS). One-sided P values were calculated per the hypothesized positive association between immune signatures and improved clinical outcomes. Results: 21 patients were identified. Mean age 64 years (yrs) with a 2:1 gender ratio (M=14; F=7). Most common primary locations - pancreas (PNEC = 8) and esophagus (3). ORR = 78.6%. TME trends were dampened anti-cancer immune response in patients >60 yrs old and <6-month OS on treatment. TME gene signatures of age >60 yrs (vs. <60 yrs), were indicative of fewer neutrophils, myeloid cells, CD8+ T-cells and CD45+ cells. Downregulated genes in the >60yr old population associated with dampened immune response - ICAM1, TNFAIP6, TWIST1, and PTGER4. A smaller natural killer (NK) cell gene signature was the only notable association with OS <6 months (vs. >6 month). Downregulated genes in >6-month population were HK2 and REN while upregulated genes included CX3CR1, ZAP70, KLRK1, XCL1/2, and MMP7 (immunostimulatory). Increased immune infiltration was associated with prolonged OS, with elevated gene signature of T-cells, lymphoid cells, mast cells, and cytotoxic cells. Downregulated genes related to poor OS were HNF1A and ESR1 (immunosuppressive). A greater potential for a tumor adaptive immune resistance/response were noted; age <60 yrs and prolonged OS having elevated TME PD-L1 and PD-1/TIGIT gene signatures respectively. PNEC was associated with elevated gene signatures of TME MHCII vs. non-PNEC. Upregulated genes in non-PNEC include CXCL2/3 while downregulated genes include TMEM173, IFI16 and RELN (diminished adaptive immune response). Conclusions: This pilot study identified trends in gene expression associated with clinical outcomes. While statistical significance was precluded by limited sample size, our results suggest trends toward increased TME immune cell infiltration in age <60yrs and prolonged OS, increased potential for adaptive immune responses in PNEC, and elevated NK cell infiltration in patients with >6 month OS. Rational drug development for affected patients should target these specific abnormalities.

The Tumor-Specific Immune Landscape in HPV+ Head and Neck Cancer.

Human papillomaviruses (HPVs) are the causative agent of several anogenital cancers as well as head and neck cancers, with HPV+ head and neck squamous cell carcinoma (HNSCC) becoming a rapidly growing public health issue in the Western world. Due its viral etiology and potentially its subanatomical location, HPV+ HNSCC exhibits an immune microenvironment which is more inflamed and thus distinct from HPV-negative HNSCC. Notably, the antigenic landscape in most HPV+ HNSCC tumors extends beyond the classical HPV oncoproteins E6/7 and is extensively targeted by both the humoral and cellular arms of the adaptive immune system. Here, we provide a comprehensive overview of HPV-specific immune responses in patients with HPV+ HNSCC. We highlight the localization, antigen specificity, and differentiation states of humoral and cellular immune responses, and discuss their similarities and differences. Finally, we review currently pursued immunotherapeutic treatment modalities that attempt to harness HPV-specific immune responses for improving clinical outcomes in patients with HPV+ HNSCC.

Dynamic changes of phenotype and function of natural killer cells in peripheral blood before and after thermal ablation of hepatitis B associated hepatocellular carcinoma and their correlation with tumor recurrence

BackgroundThermal therapy induces an immune response in patients with hepatocellular carcinoma (HCC), but the dynamic characteristics of the natural killer (NK) cell immune response post-thermal ablation remain unclear. We conducted a prospective longitudinal cohort study to observe the dynamic changes of phenotype and function of NK cells in peripheral blood before and after thermal ablation of hepatitis B-associated HCC and their correlation with tumor recurrence.MethodsFifty-six patients clinically and pathologically confirmed with hepatitis B-associated HCC were selected for thermal ablation. Peripheral blood was collected on day 0, day 7, and month 1. NK cell subsets, receptors, and killing function were detected by flow cytometry, and the LDH levels were examined. Overall recurrence and associated variables were estimated using Kaplan–Meier, log-rank, and Cox proportional-hazards analyses.ResultsThe frequency of CD3−CD56+ cells was increased on day 7 (P < 0.01) without significant differences between D0 and M1. NKG2D, NKp44, NKp30, CD159a, and CD158a expression was increased on M1 (all P < 0.05). The granzyme B and IFN-γ expression in NK cells were higher on M1 vs. D0 (P < 0.05). On day 7, the NK cell lysis activity of the target K562 cells was increased (P < 0.01) but decreased on M1 (P < 0.05). Survival analysis showed that CD158a expression and IFN-γ and perforin release on day 0 were associated with the risk of HCC recurrence. Cox regression analysis showed that the expression changes in CD56, NKp46, granzyme B, and perforin (D7-D0) induced by thermal ablation were associated with recurrence-free survival (RFS) of patients with HCC.ConclusionThermal ablation increased the frequency and function of CD3−CD56+ NK cells in the peripheral blood of patients with HCC. These cells tended to be more differentiated and activated. Notably, expression levels of NK cell receptors NKp46, perforin, and granzyme B were associated with RFS.

Current opportunities to improve outcomes of COVID-19 infection prevention and course in patients with lymphoproliferative diseases (regional analysis)

Background. Impaired immune response in patients with lymphoproliferative diseases (LPD) can lead to severe COVID-19 infection and significantly affect survival by increasing the risk of death. The effectiveness of vaccines may be reduced in people with compromised immune system function. Sequential vaccination does not ensure the production of sufficient antibodies in patients with hematological malignancies. Patients with LPD need additional measures to prevent COVID-19 infection.The high efficacy of monoclonal antibodies combinations to the SARS-CoV-2 S-protein for COVID-19 infection prevention and treatment has been shown in clinical trials. The complex use of active and passive immunization in immunocompromised patients requires confirmation in real clinical practice.Aim. A comparative analysis of COVID-19 infection severity and prevention effectiveness in patients with LPD.Materials and methods. The retrospective analysis included 200 patients with LPD who received induction therapy in R epublican Clinical Oncological Dispensary (Ufa) from 01.09.2021 to 01.09.2022. All patients received the Gam-COVID-Vac vaccine (Sputnik V, National Research Center for Epidemiology and Microbiology named after Honorary Academician N . F . Gamaleya, Ministry of Health of Russia). Patients were divided 1:1 into 2 groups matched by gender, age, LPD immunophenotype, history of previous treatment. In the 1st group, in order to pre-exposure prophylaxis of COVID-19 infection, in addition to the Gam-COVID-Vac vaccine, 2 recombinant monoclonal antibodies were administered – 150 mg tixagevimab + 150 mg cilgavimab intramuscularly. In both groups, the frequency of COVID-19 infection, the frequency of viral pneumonias identified and not identified as COVID-19 infection, the number of hospitalizations due to infection, and overall mortality were analyzed. SARS-CoV-2 positive tests results, symptoms of acute respiratory disease, the frequency of pneumonia, the number of hospitalizations for viral pneumonias, and the total mortality over a period of 4 months were recorded in the ProMed electronic medical system.Results. The patient groups were balanced by age (55 and 58 years, respectively), gender, pretreatment and use of anti-CD20 monoclonal antibodies (67 and 68 %), spectrum of nosologies: Hodgkin’s lymphoma in the 1st group was diagnosed in 21 %, in the 2nd – in 20 % of patients; diffuse large B-cell lymphoma – in 36 and 35 % of patients, respectively; follicular lymphoma – in 16 % of patients in each group; marginal zone lymphoma – in 14 % of patients in each group; mantle cell lymphoma – in 2 % of patients in each group; chronic lymphocytic leukemia – in 8 and 9 % of patients, respectively; peripheral T-cell lymphoma – in 3 % of patients in each group.The combination of tixagevimab 150 mg + cilgavimab 150 mg reduced the incidence of COVID-19 infection by almost 12 times: 59 % of patients in the 2nd group developed COVID-19 infection, while in the 1st group it was observed only in 5 % of patients, in addition, in patients of the 1st group, the infection was mild in more than half of the cases, while in the 2nd group, 2 / 3 of the patients developed viral pneumonia.The frequency of hospitalizations due to the severe course of COVID-19 infection in the 1st group was 9 times lower – 3 % versus 28 % in the 2nd group.The use of tixagevimab 150 mg + cilgavimab 150 mg combination reduced the frequency of deaths by 30 times: in the 1st group, 1 (1 %) patient died, in the 2nd group – 30 (30 %). No mortality from COVID-19 infection has been reported with the combination of tixagevimab 150 mg + cilgavimab 150 mg.The only lethal outcome in the 1st group was due to the progression of oncohematological disease. Among the 30 patients who died in 2nd group, almost half (46 %) died due to COVID-19 infection. In 2nd group, 3 (3 %) patients died from decompensation of concomitant diseases, which indirectly indicates a decrease in the risk of death with the use of additional prophylaxis in LPD patients.Conclusion. Additional prophylaxis of COVID-19 infection in oncohematological patients with the combination of monoclonal antibodies tixagevimab 150 mg + cilgavimab 150 mg (Evusheld) significantly improves outcomes by reducing the risk of infection, severe course and death from COVID-19. Reducing these risks allows patients to receive complete treatment course, without violation of the time intervals between courses, ensuring the expected overall survival.COVID-19 infection in any clinical form, including asymptomatic, delays antitumor treatment, which reduces overall survival. The use of Evusheld also reduces the risk of death from other comorbid conditions.

Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.

Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), andT-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR. The immune-checkpoint receptors PD-1, CTLA-4, LAG-3, and TIGIT on Tor NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T cells (CD3+) and T-cell subsets including, CD4+ T cells, CD8+ T cells, and T-regs, in patients who relapsed in comparison with those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available data sets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune-checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in patients with CML stopping TKI, while concomitantly targeting leukemic stem cells and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in patients with CML.

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor's microenvironment by immune cells with either regulatory or cytotoxic properties. Whether this response is associated with tumor eradication after radiotherapy and chemotherapy or regrowth has been a matter of extensive research through the years, mainly focusing on tumor-infiltrating lymphocytes and monocytes and their subtypes, and the expression of immune checkpoint and other immune-related molecules by both immune and cancer cells in the tumor microenvironment. A literature search has been conducted on studies dealing with the immune response in patients with rectal cancer treated with neoadjuvant radiotherapy or chemoradiotherapy, assessing its impact on locoregional control and survival and underlying the potential role of immunotherapy in the treatment of this cancer subtype. Here, we provide an overview of the interactions between local/systemic anti-tumor immunity, cancer-related immune checkpoint, and other immunological pathways and radiotherapy, and how these affect the prognosis of rectal cancer patients. Chemoradiotherapy induces critical immunological changes in the tumor microenvironment and cancer cells that can be exploited for therapeutic interventions in rectal cancer.

Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality

IntroductionPatients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this...

A Sampling of Highlights from the Literature.

What We're Reading| May 03 2023 A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors Author & Article Information Online ISSN: 2326-6074 Print ISSN: 2326-6066 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Immunol Res (2023) 11 (5): 557. https://doi.org/10.1158/2326-6066.CIR-11-5-WWR Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record May 3 2023 Citation A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors. Cancer Immunol Res 1 May 2023; 11 (5): 557. https://doi.org/10.1158/2326-6066.CIR-11-5-WWR Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Polyclonal neoantigen-specific T-cell responses associate with anti–PD-1 benefit (from Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths via NIH Flickr) To better understand differences in the immune response in patients with metastatic melanoma who do and do not have a clinical response to anti–PD-1 therapy, Puig-Saus et al. generated neoantigen-specific T cells from 11 patients using personalized neoantigen peptide–HLA libraries. Responding and nonresponding patients had neoantigen-specific CD8+ T cells in peripheral blood and tumor that recognized a limited number of mutations, but the CD8+ T cells from those who responded to therapy were more polyclonal, with multiple neoantigen-specific T-cell receptor clonotypes for the mutations, and were detected longitudinally, highlighting important immune characteristics of a successful clinical response to anti–PD-1 therapy. Puig-Saus C, …, Ribas A. Nature 2023 March 8;615:697–704. Neutrophils have a key role in tumor control following immunotherapy (from SVG) Neutrophils can have both pro- and... You do not currently have access to this content.

Comparison of NK cell subsets, receptors and functions induced by radiofrequency ablation and microwave ablation in HBV-associated primary hepatocellular carcinoma.

Topical therapy has been shown to induce an immune response in patients with hepatocellular carcinoma (HCC). In this study, a prospective parallel group control experiment was conducted to compare the differences between radiofrequency ablation and microwave ablation in inducing the immune regulation of NK cells. Sixty patients with clinically and pathologically confirmed hepatitis B-associated hepatocellular carcinoma (HCC) were selected for thermal ablation. Patients were randomly assigned into the MWA group (n = 30) and the RFA group (n = 30). Patient's peripheral blood was isolated on days D0, D7, and month M1. NK cell subsets, receptors, and killing function were detected by flow cytometry and LDH. Student t test and rank sum test were used to compare the statistical differences between the RFA (radio frequency) and MWA (microwave) groups. The Kaplan-Meier curve and log-rank test were used to calculate the difference between the two survival curves. Comparison of the frequency of CD3-CD56+ and CD3-CD56+CD16+ in NK cells between the RFA and WMA groups showed that there was no difference in the D0, D7, M1, D7-D0, M1-D0, and M1-D7 groups. The changes of the inhibitory NK cell receptor CD159A were significantly different at D7 (P<0.05). CD107a were compared between the RFA and WMA groups, indicating that CD107a changes induced by NK cells were significantly different at D7-D0 (P<0.05). Comparison of NK cell lysis activity of target K562 cells between the RFA and WMA groups showed that there was no difference at D0, D7, D7-D0. There was no difference in recurrence-free survival (RFS) between the RFA and WMA groups (P=0.11). The difference between MWA and RFA-induced NK cell changes was mainly manifested in the inhibitory receptors CD159a and CD107a 1 week after surgery, with microwave-induced changes being more severe. Comparison of the NK cell lysis activity of the target K562 cells between the RFA and WMA groups showed that there was no difference in D0, D7, D7- D0. Survival analysis showed that these differences did not affect the recurrence-free survival (RFS) in the two groups.

Extracellular vesicles derived from the intestinal microbiota of patients with CGD-associated inflammatory bowel disease have pro-inflammatory effects

BackgroundChronic granulomatous disease (CGD) is an inborn error of immunity characterized by mutations in any one of the 6 subunits forming the nicotinamide-adenine dinucleotide phosphate oxidase complex 2 leading to defective phagocyte-derived ROS production. As a result, patients with CGD have recurrent infections and increased inflammation and 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). Although we have previously demonstrated that patients with CGD-IBD have intestinal dysbiosis, its functional impact is poorly understood. Interestingly, intestinal microbes can produce gut microbiota-derived extracellular vesicles (GMEVs) which can cross the intestinal barrier and have systemic and/or end-organ immunomodulatory effects. Yet, the role of GMEVs in patients with CGD has never been evaluated. ObjectiveTo investigate the impact of GMEVs isolated from patients with CGD, with or without CGD-IBD, on intestinal permeability and inflammatory responses using wild type and NOX2-deficient (CYBB-/-) models. MethodsGMEVs were isolated and characterized from fecal samples obtained from 11 patients without CGD-IBD and 11 patients with active CGD-IBD recruited at the National Institutes of Health. Stimulation with GMEVs was performed on HT29, THP1 and CYBB-/- THP1 cell lines, HT29/THP1 co-culture models, and induced pluripotent stem cell-derived human intestinal organoids. TNF-α, IL-6, IL-8, IL-1β, IP-10, GM-CSF and MCP1 gene expression and production were assessed by RT-qPCR and ELISA, respectively. ResultsOur data showed that stimulation with GMEVs from patients with active CGD-IBD increased intestinal permeability compared to cells stimulated with GMEVs from patients without CGD-IBD. In HT29 cells, increased intestinal permeability was associated with increased gene expression and production of IL-8 and IL-1β. IL-8 was similarly increased in intestinal organoids. In THP1 cells, stimulation led to increased gene expression and production of TNF-α, IL-6 and IP-10, while stimulation in CYBB-/- THP1 cells increased TNF-α and MCP1 gene expression. Finally, stimulation of HT29/THP1 cell co-cultures resulted in increased gene expression of TNF-α, IL-6 and GM-CSF. ConclusionsOur results suggest that GMEVs isolated from patients with CGD-IBD may induce pro-inflammatory immune responses in patients with CGD, thereby contributing to their underlying inflammatory pathology. These findings bring forward GMEVs as a possible new therapeutic target for CGD-IBD. [Display omitted]

Influence of antidiabetic drugs on glucose metabolism and immune response in patients with metastatic pancreatic ductal adenocarcinoma receiving gemcitabine plus nab-paclitaxel as first-line treatment.

Association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from AOU Cagliari Medical Oncology and 58 from AOU Ancona Medical Oncology. All patients received gemcitabine plus nab-paclitaxel first-line chemotherapy. We aimed to evaluate the correlation between DM2, anti-diabetic medications and overall survival. Survival distribution was assessed by Kaplan-Meier curves. Median age was 68±9, 127 (55%) were male. 138/232 (59%) patients were not affected by DM2, 94/232 (41%) were affected by DM2. 57 were insulin-treated and 37 were metformin-treated. DM2 treated patients showed an higher median overall survival (26vs 12 months, p=0,0002). Among DM2 patients insulin-treated and metformin-treated showed an mOS of 21 months and 33 months, respectively. Results showed a correlation between treated DM2 and higher mOS in patients with mPDAC. Limitations due to retrospective data collection must be considered. Further studies in this setting are needed.

Study on immune status alterations in patients with sepsis

Sepsis, characterized by cytokine-mediated hyper-inflammation and a consistent decline in immune responsiveness, is associated with a high risk of death in the intensive care unit (ICU). Here, we for the first time investigated the changes in immune and inflammatory responses to understand the interactions between immune and inflammatory biomarkers and their association with patient outcomes. The cytokine and lymphocyte subset levels were analyzed in healthy donors (HD) and patients with sepsis upon admission to the ICU (D0), D3, D7, D14, and D28 using flow cytometry. The primary endpoint was mortality on day 90. The trends in lymphocyte subsets and cytokine levels in all patients (n=47), HD (n=27), and patient subgroups (surviving, n=30; dead, n=17) were analyzed using an independent sample t-test and principal component analysis. Age, steroids (steroids used>48h), secondary infection, acute heart failure, acute kidney injury, coagulopathy, hypohepatia, organ transplant and septic shock (when transferred to the ICU) were associated with mortality. Absolute lymphocyte counts and lymphocyte subsets levels were reduced in most patients with sepsis. The proportion of Tregs in the patients increased with disease progression and was associated with immunosuppression. In conclusion, sepsis downregulated adaptive immunity, and induced the transition of the patients to prolonged immune suppression. The study suggests that while cellular immunity recovered within 2weeks of admission, humoral and innate immunity recovery takes longer. These findings may assist in developing appropriate therapeutic approaches to improve the immune responses in patients with sepsis.

Disease associated monocytes contribute to the inflammatory milieu in hidradenitis suppurativa and have dysregulated expression of transposable elements

Abstract Hidradenitis suppurativa (HS), an inflammatory skin-disease, manifests as painful lesions in intertriginous skin. Despite their central role in innate immunity the role of monocytes in HS is largely unknown. Here we utilized cytometry by time-of-flight (CyTOF), imaging CyTOF (IMC), cellular indexing of transcriptomes and epitopes by sequencing (CITEseq), spatial transcriptomics (ST), and our recently developed database (HSOmicsDB) to characterize the systemic and cutaneous immune response in patients with HS. CITEseq found differential genes in circulating immune cells from HS patients enriched for cellular activation and extravasation. CyTOF immune profiling of fresh whole-blood samples found decreased frequency of classical Mos (C.Mos), which had increased expression of skin homing chemokine receptors. IMC found C.Mos infiltrated lesional dermis and tunnel regions, but not perilesional (PL) skin. Patients with HS showed increased proportions of activated C.Mo subclusters and a population of SOD2+ C.Mos expressing genes downstream of viral sensing pathways. SOD2 +C.Mos expressed high levels of neutrophil attracting chemokines. ST found SOD2 +C.Mos localized to regions of active inflammation and dermal tunnels. HSOmicsDB showed Mos and Macs expressed SOD2 +C.Mo genes, which were enriched in lesions, but not PL skin. Finally, we show that SOD2 +C.mos in HS have dysregulated expression of transposable elements (TEs), which may be activating viral sensing mechanisms in patients with HS. Together our data shows monocytes in HS function to recruit neutrophils to lesional HS skin, and provides the first evidence implicating TEs as disease promoting factors in HS by leading to C.Mo dysregulation. Supported By NIH/NIAMS, R01AR078688-01A1 and R21AR079089-01A1

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

The recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). We retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL). Although active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3. This study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response.

Differences in immune response in patients with chronic opisthorchiasis invasion related to clinical manifestations of hepatobiliary system diseases

The aim of the study was to identify differences in the immune response in chronic opisthorchiasis with or without clinical manifestations of hepatobiliary system diseases. A comparison of laboratory parameters of immune system functioning (lymphocyte phenotypes detected by flow cytometry, concentrations of immunoglobulins and cytokines, indicators of nonspecific resistance) in patients with chronic opisthorchiasis (caused by Opisthorchis felineus) lacking clinical manifestations and with manifestations of cholecystitis, cholangitis, pancreatitis, gastritis, gastroduodenitis, confirmed by ultrasound and FGDS. It was found that the immunological parameters of the innate immune response were increased in all patients with chronic opisthorchiasis compared with the control group of apparently healthy subjects, which indicates activated macrophage-phagocytic arm in patients with opisthorchiasis invasion. The indicator of the stimulated NBT test is maximal in chronic opisthorchiasis without hepatobiliary system diseases, in case of comorbidity with such diseases it declines, but remains significantly higher than the values of the control group. This may be due to the exhaustion in the reserve capabilities of bactericidal neutrophil systems in patients with symptoms of damage to the hepatobiliary system due to prolonged inflammation. Indicators of the cellular arm in patients with chronic opisthorchiasis without clinical manifestations of hepatobiliary system diseases demonstrate a decrease in the absolute and relative level of cytotoxic T-lymphocytes. In the group with picture of hepatobiliary system disorders, an even deeper imbalance of indicators is revealed: the relative and absolute level of lymphocytes, the absolute count of T-lymphocytes are reduced, which may indicate about involvement of cellular immunity in the pathogenesis of complications of chronic opisthorchiasis. In all examined patients with chronic opisthorchiasis, the humoral immune response was also activated the total immunoglobulin E was significantly increased; at the same time, in patients with hepatobiliary system lesions, this parameter increases even more and a decrease in B-lymphocytes is detected. In all patients with chronic opisthorchiasis, there is also an increased level of proinflammatory cytokine IL-8, which rises even more in the group with hepatobiliary system diseases. The data obtained indicate the involvement of all arms of the immune response in a prominent inflammatory process when chronic opisthorchiasis is complicated by clinically overt hepatobiliary system diseases: the degree of deviation in the indicators of the innate and adaptive immune response from the norm and from those in uncomplicated opisthorchiasis increases.

The effect of omega-3 fatty acids supplementation on inflammatory biomarkers in subjects with migraine: a randomized, double-blind, placebo-controlled trial

Objective Imbalances in immune regulation are important features of migraine pathophysiology. In line with this, the current study investigated the efficacy of omega-3 fatty acids supplementation on inflammatory and anti-inflammatory markers in patients with migraines. Materials and Methods This randomized, double-blind, placebo-controlled trial consisted of 40 patients that were prone to experiencing episodic migraines. For two months, participants were randomized into one group that received omega-3 supplementation (n= 20), 600 mg of EPA and 300 mg of DHA, twice daily) or another group that received a placebo (n= 20). Transforming growth factor β (TGF-β), interleukin (IL)-4, interferon-gamma (IFN-γ), and interleukin (IL)-17 serum levels were assessed using enzyme-linked immunosorbent assay methods at baseline and following the intervention. The current study was registered on ClinicalTrials.gov with the registration number NCT02532023. Results After two months of intervention, the administration of omega-3 fatty acids resulted in a significant rise in the concentrations of anti-inflammatory cytokine IL-4 (p=0.010) as well as a significant reduction in concentrations of pro-inflammatory cytokine IFN-γ (p=0.001) compared with the placebo. However, no significant changes were observed in serum TGF-β and IL-17 levels. Discussion Our findings indicated consumption of omega-3 fatty acids may have a potentially beneficial response on the inflammatory immune response in patients with migraines. Larger trials are needed to corroborate these findings.

In Memoriam: Soldano Ferrone MD, PhD (1940–2023)

In Memoriam: Soldano Ferrone MD, PhD (1940–2023)

Dynamics of changes in immunological parameters in adults with COVID-19

Aim. To evaluate the immune response in patients with COVID-19 and to track the dynamics of changes in immunological parameters 2-3 weeks after the onset of the disease. Materials and methods. The study included the results of a survey of 55 people aged 19 to 55 years with a new coronavirus infection (NCVI, COVID-19) in 2020. 27 of them were re-examined. The first sample (n=55) was taken on average 4.3 ± 0.49 days from the onset of the disease, the second (n=27) – 12.7 ± 1.12 days. The control group consisted of practically healthy individuals (n=41). The following indicators were determined in all patients: the presence of SARSCoV-2 RNA, the parameters of the general blood test, the main subpopulations of lymphocytes, the level of total immunoglobulins (IgM, IgG, IgA), the number of CEC, the absorption and bactericidal activity of leukocytes, the level of specific IgM and IgG to SARS-CoV-2. Results. At the onset of the disease, a statistically significant decrease in the level of lymphocytes (p&lt;0.001) and their subpopulations (TNK cells (p&lt;0.001), T-helper lymphocytes (&lt;0.001), cytotoxic T-lymphocytes (p&lt;0.001), NK cells (&lt;0.001) and T-lymphocytes (&lt;0.001)). At the same time, the level of activated T-lymphocytes was statistically significantly higher (p&lt;0.001) than the same indicator in the control group. When analyzing immunological parameters after 12.7±1.12 days, an increase in the total number of lymphocytes (p&lt;0.001), T-lymphocytes (p=0.003), T-helper cells (p=0.015) was found; an increased content of activated T-lymphocytes (p&lt;0.001) and a low level of TNK cells (p&lt;0.001). The indicators of the phagocytic link in patients with COVID-19 in the first days of the disease were within the reference range (similar indicators in the control group). Repeated examination of patients (sample 2) showed an increase in the phagocytic activity of leukocytes and monocytes (p&lt;0.003 and p&lt;0.09, respectively). At the beginning of the disease, already on the 4th-5th day of the disease, specific IgM and IgG antibodies to SARS-CoV-2 were detected in the blood serum of patients, by the second week of the disease their level was significantly higher than in the first study (p&lt;0.009). Conclusion. At the onset of the disease, insufficiency of the cellular link of immunity was noted, which is probably as sociated with a violation of immunoregulatory mechanisms. At the same time, an increase in the level of activated T-lymphocytes indicates an overactivation of immune reactions, i.e. it can be said that there is an imbalance in the immune response in COVID-19.

Evaluation of the interaction between tumor growth factor-β and interferon type I pathways in patients with COVID-19: focusing on ages 1 to 90 years

BackgroundEvidence revealed that age could affect immune responses in patients with the acute respiratory syndrome of coronavirus 2 (SARS-CoV-2) infection. This study investigated the impact of age on immune responses, especially on the interaction between the tumor growth factor-β (TGF-β) and interferon type-I (IFN-I) axes in the pathogenesis of novel coronavirus disease 2019 (COVID-19).MethodsThis age-matched case–control investigation enrolled 41 COVID-19 patients and 40 healthy controls categorized into four groups, including group 1 (up to 20 years), group 2 (20–40 years), group 3 (40–60 years), and group 4 (over 60 years). Blood samples were collected at the time of admission. The expression of TGF-βRI, TGF-βRII, IFNARI, IFNARII, interferon regulatory factor 9 (IRF9), and SMAD family member 3 (SMAD3) was measured using the real-time PCR technique. In addition, serum levels of TGF-β, IFN-α, and SERPINE1 were measured by the enzyme-linked immunosorbent assay (ELISA) technique. All biomarkers were measured and analyzed in the four age studies groups.ResultsThe expression of TGF-βRI, TGF-βRII, IFNARI, IFNARII, IRF9, and SMAD3 was markedly upregulated in all age groups of patients compared with the matched control groups. Serum levels of IFN-α and SERPINE1 were significantly higher in patient groups than in control groups. While TGF-β serum levels were only significantly elevated in the 20 to 40 and over 60 years patient group than in matched control groups.ConclusionsThese data showed that the age of patients, at least at the time of admission, may not significantly affect TGF-β- and IFN-I-associated immune responses. However, it is possible that the severity of the disease affects these pathway-mediated responses, and more studies with a larger sample size are needed to verify it.

The relationship of lymphoid populations (infiltration) of the primary tumor with bone marrow immune responses in patients with breast cancer

Backgraund. Currently, immunotherapy is firmly established in the standard of cancer treatment. The basis for the appointment of immunotherapy are immunological tumor markers, which include lymphoid infiltration, a detailed study of which has received increasing attention in the last decade. An undoubted interest is the study of lymphoid infiltration, not only depending on the morpho-clinical parameters of breast cancer (BC), but also on the immune system of the bone marrow.Aim. To evaluate the infiltration of the primary tumor by lymphocytes depending on the morpho-clinical characteristics of BC and immune responses in the bone marrow.Materials and methods. This study included 125 patients with BC who received treatment at the “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of Russia. Tumor stage II was prevailed, а moderate degree of differentiation (G2) was more often noted. The luminal BC – 67 %, non-luminal – 33 %. Immunophenotyping of the primary tumor: cryostat sections, ZEISS Axioscope luminescent microscope (Zeiss AG, Germany). CD45+, CD38+, T- and B-cell infiltration were assessed. Bone marrow: CD3+, CD4+, CD8+, CD19+, CD16+, CD56+ lymphocytes and their subpopulations were studied (FACSCanto II flow cytometer, Kaluza Analysis v2.1 program (Beckman Coulter, USA)).Results. CD45+ infiltration was noted in 50.5 % of cases (severe in 30 %, moderate – 26.4 %). CD8+ cells significantly infiltrated the tumor in 21.4 % of cases. CD38+ infiltration was observed in 40 %. In the non-luminal BC, severe CD45 infiltration was observed more frequently than in the luminal (33 % vs 26 %). CD38+ infiltration is expressed in non-luminal BC (p = 0.016). CD45+ infiltration was positively correlated with earlier stages (p = 0.071) more pronounced in infiltrative ductal BC, than in lobular BC: 59.2 % vs 20 % (p = 0.05). The content of CD45RO+cells in bone marrow in the luminal BC is higher than in the non-luminal: 37.3 ± 2.3 % vs 28 ± 2.8 % (p = 0.04). The number of CD19+CD38+ cells, on the contrary, is less: 24.2 ± 2 % vs 34.8 ± 6 % (p = 0.041). Tumor-infiltrating lymphocytes highly correlated with bone marrow lymphoid populations: CD38+ cells with NK-bone marrow cells; CD4+ cells with the B-precursors; CD8+cells with the B1-lymphocytes.Conclusion. Lymphoid infiltration of BC is associated with stage, tumor size, histological type and biological subtype. Intratumoral populations CD38+, CD4+, CD3+, CD8+ cells are in a negative correlation with bone marrow lymphoid populations.