Evaluation of the Abdala Vaccine: Antibody and Cellular Response to the RBD Domain of SARS-CoV-2.

Abdala is a recently released RBD protein subunit vaccine against SARS-CoV-2. A few countries, including Mexico, have adopted Abdala as a booster dose in their COVID-19 vaccination schemes. Despite that, most of the Mexican population has received full-scheme vaccination with platforms other than Abdala; little is known regarding Abdala's immunological features, such as its antibody production and T- and B-cell-specific response induction. This work aimed to study antibody production and the adaptive cellular response in the Mexican population that received the Abdala vaccine as a booster. We recruited 25 volunteers and evaluated their RBD-specific antibody production, T- and B-cell-activating profiles, and cytokine production. Our results showed that the Abdala vaccine increases the concentration of RBD IgG-specific antibodies. Regarding the cellular response, after challenging peripheral blood cultures with RBD, the plasmablast (CD19+CD27+CD38High) and transitional B-cell (CD19+CD21+CD38High) percentages increased significantly, while T cells showed an increased activated phenotype (CD3+CD4+CD25+CD69+ and CD3+CD4+CD25+HLA-DR+). Also, IL-2 and IFN-γ increased significantly in the supernatant of the RBD-stimulated cells. Our results suggest that Abdala vaccination, used as a booster, evokes antibody production and the activation of previously generated memory against the SARS-CoV-2 RBD domain.

Transcriptional signature of early cisplatin drug-tolerant persister cells in lung adenocarcinoma.

Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.

Obesity Contributes to Inflammation in Patients with IBS via Complement Component 3 and C-Reactive Protein.

Irritable Bowel Syndrome (IBS) is usually a lifelong state that disturbs the digestive system. IBS has been linked to low-grade inflammation and the release of inflammatory mediators into the bloodstream. This could be associated with the degree of obesity presented by patients with IBS. Reports imply that IBS is more frequent in obese patients than in the overall population, with a prevalence of up to 31%. Here, we evaluated the serum levels of immunological and inflammation molecules and their correlation with Body Mass Index in IBS patients and the healthy control (HC). Seventy-nine serum samples of the IBS patients and thirty-five of the HC group were analyzed to determine the levels of each molecule and compare them with their BMI. Serum levels of C3 and C4 were significantly increased in IBS patients. C3 and C4 levels were higher in IBS-M and IBS-D subtypes compared with the HC group. When patients were grouped by BMI, a positive correlation between serum C3 (r = 0.49, p < 0.0001) and CRP (r = 0.40, p < 0.001) levels was found. Our results show, for the first time, a correlation between immunological molecules and BMI in IBS patients, suggesting that the inflammatory nature of obesity could contribute to the development of the symptoms in IBS through the stimulation and release of proteins as complement components and CRP.

Effector-Memory B-Lymphocytes and Follicular Helper T-Lymphocytes as Central Players in the Immune Response in Vaccinated and Nonvaccinated Populations against SARS-CoV-2.

Vaccines have been recognized as having a central role in controlling the COVID-19 pandemic; however, most vaccine development research is focused on IgG-induced antibodies. Here, we analyzed the generation of IgGs related to SARS-CoV-2 and the changes in B- and T-lymphocyte proportions following vaccination against COVID-19. We included samples from 69 volunteers inoculated with the Pfizer-BioNTech (BNT162b2), Astra Zeneca (AZD1222 Covishield), or Sputnik V (Gam-COVID-Vac) vaccines. IgGs related to SARS-CoV-2 increased after the first vaccine dose compared with the nonvaccinated group (Pfizer, p = 0.0001; Astra Zeneca, p < 0.0001; Sputnik V, p = 0.0089). The results of the flow cytometry analysis of B- and T-lymphocytes showed a higher proportion of effector-memory B-lymphocytes in both first and second doses when compared with the nonvaccinated subjects. FcRL4+ cells were increased in second-dose-vaccinated COVID-19(−) and recovered COVID-19(+) participants when compared with the nonvaccinated participants. COVID-19(−) participants showed a lower proportion of follicular helper T-lymphocytes (TFH) in the second dose when compared with the first-vaccine-dose and nonvaccinated subjects. In conclusion, after the first vaccine dose, immunization against SARS-CoV-2 induces IgG production, and this could be mediated by TFH and effector-memory B-lymphocytes. Our data can be used in the design of vaccine schedules to evaluate immuno-bridging from a cellular point of view.

Old and New Players of Inflammation and Their Relationship With Cancer Development.

Pathogens or genotoxic agents continuously affect the human body. Acute inflammatory reaction induced by a non-sterile or sterile environment is triggered for the efficient elimination of insults that caused the damage. According to the insult, pathogen-associated molecular patterns, damage-associated molecular patterns, and homeostasis-altering molecular processes are released to facilitate the arrival of tissue resident and circulating cells to the injured zone to promote harmful agent elimination and tissue regeneration. However, when inflammation is maintained, a chronic phenomenon is induced, in which phagocytic cells release toxic molecules damaging the harmful agent and the surrounding healthy tissues, thereby inducing DNA lesions. In this regard, chronic inflammation has been recognized as a risk factor of cancer development by increasing the genomic instability of transformed cells and by creating an environment containing proliferation signals. Based on the cancer immunoediting concept, a rigorous and regulated inflammation process triggers participation of innate and adaptive immune responses for efficient elimination of transformed cells. When immune response does not eliminate all transformed cells, an equilibrium phase is induced. Therefore, excessive inflammation amplifies local damage caused by the continuous arrival of inflammatory/immune cells. To regulate the overstimulation of inflammatory/immune cells, a network of mechanisms that inhibit or block the cell overactivity must be activated. Transformed cells may take advantage of this process to proliferate and gradually grow until they become preponderant over the immune cells, preserving, increasing, or creating a microenvironment to evade the host immune response. In this microenvironment, tumor cells resist the attack of the effector immune cells or instruct them to sustain tumor growth and development until its clinical consequences. With tumor development, evolving, complex, and overlapping microenvironments are arising. Therefore, a deeper knowledge of cytokine, immune, and tumor cell interactions and their role in the intricated process will impact the combination of current or forthcoming therapies.

IL-6, NLR, and SII Markers and Their Relation with Alterations in CD8+ T-Lymphocyte Subpopulations in Patients Treated for Lung Adenocarcinoma.

Cytokines, key contributors to tumorigenesis, are mediators between inflammatory immune or nonimmune and cancer cells. Here, IL-6 production by tumor cells was assessed in a cohort of patients with lung adenocarcinoma treated with conventional therapy. IL-6 levels and neutrophil-lymphocyte ratio (NLR) or systemic immune-inflammation index (SII) markers were evaluated. Changes in pro- and anti-inflammatory cytokines, HMGB1 concentration, and CD4+ and CD8+ T-lymphocyte populations and their subpopulations were investigated. IL-6 expression was detected immunohistochemically in lung adenocarcinoma biopsies. Cytokines were quantified using the cytometric bead array, and TGF-ß and HMGB-1 through ELISA. Clinical parameters were collected to assess NLR and SII. CD4+ and CD8+ T-lymphocytes and naïve, memory, and effector subpopulations were quantified by flow cytometry. The data obtained were associated with patients' median overall survival (OS). IL-6 showed the highest increase, probably because the lung adenocarcinoma cells produced IL-6. Patients with higher OS had lower NLR and SII from the third cycle of chemotherapy. Patients with lower OS had significantly lower percentages of CD8+ T-lymphocyte and its effector subpopulations, with a concomitant increase in the naïve subpopulation. This study suggests that in addition to the known inflammatory markers, IL-6, CD8+ T-lymphocytes and their effector and naïve subpopulations could be useful as predictive markers in lung adenocarcinoma.

LAP TGF-Beta Subset of CD4(+)CD25(+)CD127(-) Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients.

Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4(+) T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-ß subset of CD4(+)CD25(+)CD127(-) Treg cells, which overexpressed LAP TGF-ß. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-ß subset of CD4(+)CD25(+)CD127(-) Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells.

Relationship of dendritic cell density, HMGB1 expression, and tumor-infiltrating lymphocytes in non-small cell lung carcinomas.

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) is the most common type of lung carcinomas. In adenocarcinomas, the most frequent histologic type of NSCLC, dendritic cells (DCs) are localized in close contact with tumor cells, and tumor-infiltrating lymphocytes (TILs) are observed in the peritumoral zones. In NSCLC, no studies investigating the density of intratumoral DCs and their impact on the density of TILs have been performed. In addition, the role of the alarmin high-mobility group box1 (HMGB1) in intratumoral DCs recruitment has not been analyzed. In the present study, a total of 82 cases of advanced stages of NSCLC were included. Tissue samples were obtained from biopsies and autopsies. DCs in biopsies or combinations of DCs and NK cells, CD3 T lymphocytes, or CD8 T lymphocytes from autopsy specimens were quantified in high power fields. Also, distribution of HMGB1 in tumor cells was detected. In lung adenocarcinomas, irrespective of subclassification, high densities of infiltrating DCs directly associated to high densities of peritumoral TILs. A 2.5-fold increase in TILs was found in specimens with high densities of infiltrating DCs compared with TILs from adenocarcinomas with low densities of infiltrating DCs. High densities of infiltrating DCs were associated with lung adenocarcinomas expressing cytoplasmic or nuclear-cytoplasmic HMGB1. Our results suggest that in adenocarcinoma patients, HMGB1 produced by tumor cells recruits DCs, which associate to an increase of TILs. Encouraging tumor-DCs-T lymphocytes interactions should improve the quality of life and survival of NSCLC patients.