Immunological Modulation Research Articles

Prognostic and immunotherapeutic significance of mannose receptor C type II in 33 cancers: An integrated analysis.

Background: The type 2 mannose receptor C (MRC2) is involved in tumor biological processes and plays a new role in the remodeling of the extracellular matrix turnover. Previous studies have demonstrated MRC2 expression profiling and prognostic relevance in some tumor types. However, the clinical and immunotherapeutic value of MRC2 in pan-cancers remains controversial. Our study aimed to evaluate MRC2 expression pattern, clinical characteristics and prognostic significance in 33 cancers, explore the relationship between MRC2 and immune-related characteristics, and assess the prediction of MRC2 for the immunotherapeutic response. Methods: Transcriptional and clinical data of 33 cancers were downloaded from The Cancer Genome Atlas database (TCGA) database and two independent immunotherapeutic cohorts were obtained from GSE67501 and the IMvigor210 study. Next, patients stratified by MRC2 expression levels were displayed by Kaplan-Meier plot to compare prognosis-related indexes. Meanwhile, immune infiltrates of different cancers were estimated by tumor immune estimation resources (TIMER) and CIBERSORT. The ESTIMATE algorithm was used to estimate the immune and stromal scores in tumor tissues. MRC2 expression and immunological modulators, including immune inhibitors, immune stimulators, and MHC molecules, were screened through the TISIDB portal. Gene-set enrichment analysis analyses were performed to explore the underlying biological process of MRC2 across different cancers. The immunotherapeutic response prediction was performed in two independent cohorts (GSE78220: metastatic melanoma with pembrolizumab treatment and IMvigor210: advanced urothelial cancer with atezolizumab intervention). Results: MRC2 is expressed differently in many cancers and has been shown to have potential prognostic predicting significance. MRC2 was significantly associated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Notably, the immunotherapeutic response group was associated with lower MRC2 expression in metastatic melanoma and advanced urothelial carcinoma cohort. Conclusion: This study demonstrated that MRC2 could be a prognostic indicator for certain cancer and is critical for tumor immune microenvironments. MRC2 expression level may influence and predict immune checkpoint blockade response as a potential indicator.

Adaptive immunity in different CT patterns of active tuberculosis and possible variability according to patients' geographic provenience.

BackgroundIt is still unclear if low lymphocyte levels are directly related to immunological modifications induced by the TB infection or if they depend on the general pre-existing health impairment of affected patients. Our aim was to detect eventual differences in the immunological status of patients with pulmonary TB compared to an age and sex-matched group of hospitalized patients with other bacterial community-acquired pneumonia (CAP). In addition, we tried to assess an association between alterations in the peripheral lymphocyte subsets and the development of different CT patterns of active TB and to discover differences in the immunological status and in the radiological patterns of TB presentation between patients of different geographic proveniences.MethodsThis observational study included 48 patients with TB and 48 sex- and age-matched patients affected by other bacterial CAP. The presence of HIV/AIDS, other immunocompromising conditions, and confounding chronic pulmonary comorbidities was excluded. Flow cytometry was performed on all the enrolled subjects at admission, before starting the appropriate antibiotic therapy. Patients with TB also underwent a computed tomography (CT) scan.ResultsPatients with TB showed a decrease in the absolute count of all the lymphocyte subsets compared to the CAP group. Only the reduction in the percentage of CD4+ T-lymphocytes was significant, while the percentage of CD8+ T-lymphocytes was significantly increased. Patients presenting exudative forms with atypical locations of TB showed a significant reduction in the absolute count and percentage of CD19+ B-lymphocytes compared to those affected by productive TB forms with the typical location. Despite being younger, our black Sub-Saharan Africans showed a significant reduction in the CD4+ T-lymphocytes compartment and a higher prevalence of atypical and exudative forms of TB compared with white Europeans.ConclusionTuberculosis itself may alter peripheral blood lymphocyte subsets compared to other CAP. An impaired CD19+ B-lymphocyte compartment may result in an abnormal exudative response in atypical locations and a suboptimal bacterial control. Other constitutive or environmental causes may influence immunological differences found in patients with TB, particularly in case of different geographic origins. Anyhow, flow cytometry may be of great value in evaluating the immune function of these patients.

111P Interim biomarker analysis of a phase Ib/II study of anti-TIGIT etigilimab (MPH313) and nivolumab in subjects with select locally advanced or metastatic solid tumors (ACTIVATE)

111P Interim biomarker analysis of a phase Ib/II study of anti-TIGIT etigilimab (MPH313) and nivolumab in subjects with select locally advanced or metastatic solid tumors (ACTIVATE)

Sirpiglenastat (DRP-104) Induces Antitumor Efficacy through Direct, Broad Antagonism of Glutamine Metabolism and Stimulation of the Innate and Adaptive Immune Systems.

Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor immune evasion. As such, the broad antagonism of glutamine in tumors and the tumor microenvironment may lead to direct antitumor activity and stimulation of antitumoral immune responses. DRP-104 (sirpiglenastat) was designed as a novel prodrug of the broad-acting glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). DRP-104 is an inactive form that is preferentially converted to DON within tumors. Metabolomic profiling of tumors treated with DRP-104 revealed widespread changes indicative of the disruption of tumor anabolism and canonical cancer metabolism pathways; including altered glutamine metabolism while several immunosuppressive metabolites were decreased. Gene expression profiling revealed broad immunological modulation, confirmed by flow cytometry indicating that DRP-104 treatment resulted in substantial and broad changes in various immune cell infiltrates, such as increased TIL, T, NK, and NK T cells. Functionally, T cells became more proliferative and less exhausted; tumor-associated macrophages were polarized to the M1 phenotype; MDSCs and protumorigenic proteins were decreased in TME. Finally, DRP-104 demonstrated significant antitumor activity as a monotherapy, which was further enhanced in combination with checkpoint blockade therapies, leading to improved survival and long-term durable cures. In summary, DRP-104 broadly remodels the tumor microenvironment by inducing extensive tumor metabolism effects and enhancing the infiltration and function of multiple immune cells distinct from those obtained by checkpoint inhibitor therapy. This unique mechanism of action supports the ongoing clinical development of DRP-104 alone and in combination with checkpoint inhibitors.

INCIDENCE AND GRAVITY OF COVID-19 IN PATIENTS WITH ALLERGIC RHINITIS UNDER TREATMENT WITH SUBLINGUAL IMMUNOTHERAPY

Introduction: Coronavirus disease (COVID-19) is a systemic, immunological, contagious and lethal disorder, with predominantly respiratory manifestations, caused by human infection by the SARS-CoV-2 virus. Allergic rhinitis (AR), in turn, is an incurable and heterogeneous disease, characterized as an inflammation and/or dysfunction of the nasal lining mucosa. Immunotherapy is the only treatment that can lead to the cure of AR. It involves a programmed administration of allergen extract in effective doses, instituting a persistent immunological modification. It is necessary to know if the control of AR with immunotherapy causes any benefit in relation to COVID-19. Objective: To evaluate the incidence rate and severity of COVID-19 in patients with AR treated with sublingual immunotherapy, compared to patients with AR who have not undergone this type of treatment. Methods: This was a retrospective, cross-sectional observational study, carried out by means of questionnaires sent by email to patients with AR undergoing treatment at the Rhinitis and Allergy Center of the Hospital Paranaense de Otorrinolaringologia, in Curitiba (Brazil), in the period from March 2020 to March 2021. The evaluation period for these questionnaires was the month of October 2021. The research project was approved by the Ethics Committee for Research in Human Beings of the Hospital Paranaense de Otorrinolaringologia. A Free and Informed Consent Term was obtained from all participants. The results obtained in the study were described as frequencies and percentages. To compare the groups defined by treatment with sublingual immunotherapy, in relation to the categorical variables, Fisher’s exact test or the chi-square test was used. Results: Twenty patients (36.4%) with confirmed COVID-19 have not undergone independent immunotherapy treatment, against eight patients (21.1%) in the immunotherapy group. However, the difference was not statistically significant. Regarding the severity of the condition, most of the patients in both groups reported symptoms, which was also not statistically significant. Conclusion: There was no statistically significant difference for the incidence rate of COVID-19 in patients with allergic rhinitis treated with sublingual immunotherapy, compared to patients with allergic rhinitis who have not undergone this type of treatment.

Effects of Extracellular Vesicles Secreted by TGFβ-Stimulated Umbilical Cord Mesenchymal Stem Cells on Skin Fibroblasts by Promoting Fibroblast Migration and ECM Protein Production.

Umbilical cord-derived mesenchymal stem cells (UCMSCs) have been illustrated for their roles in immunological modulation and tissue regeneration through the secretome. Additionally, culture conditions can trigger the secretion of extracellular vesicles (EVs) into extracellular environments with significant bioactivities. This study aims to investigate the roles of three EV sub-populations released by UCMSCs primed with transforming growth factor β (TGFβ) and their capacity to alter dermal fibroblast functions for skin aging. Results show that three EV sub-populations, including apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXs), were separated from conditioned media. These three EVs carried growth factors, such as FGF-2, HGF, and VEGF-A, and did not express noticeable effects on fibroblast proliferation and migration. Only EX from TGFβ-stimulated UCMSCs exhibited a better capacity to promote fibroblasts migrating to close scratched wounds than EX from UCMSCs cultured in the normal condition from 24 h to 52 h. Additionally, mRNA levels of ECM genes (COL I, COL III, Elastin, HAS II, and HAS III) were detected with lower levels in fibroblasts treated with EVs from normal UCMSCs or TGFβ-stimulated UCMSCs compared to EV-depleted condition. On the contrary, the protein levels of total collagen and elastin released by fibroblasts were greater in the cell groups treated with EVs compared to EV-depleted conditions; particularly elastin associated with TGFβ-stimulated UCMSCs. These data indicate the potential roles of EVs from UCMSCs in protecting skin from aging by promoting ECM protein production.

4-(3,4-Dimethoxyphenyl)-3,6-dimethyl-2-phenyl-3,4-dihydroquinolin-1(2H)-yl)](furan-2-yl)methanone

A N-(2,4-diaryltetrahydroquinolin-1-yl) furan-2-carboxamide derivative, [4-(3,4-dimethoxyphenyl)-3,6-dimethyl-2-phenyl-3,4-dihydroquinolin-1(2H)-yl)](furan-2-yl)methanone, was synthesized in a two-step procedure from p-toluidine, benzaldehyde, and trans-methyl-isoeugenol as commercial starting reagents through a sequence of Povarov cycloaddition reaction/N-furoylation processes. The structure of the compound was fully characterized by IR, 1H, 13C-NMR, and X-ray diffraction data. Such types of derivatives are known as relevant therapeutic agents exhibiting potent anticancer, antibacterial, antifungal, anti-inflammatory, and immunological modulator properties.

Low Molecular Weight Sericin Enhances the In Vitro of Immunological Modulation and Cell Migration.

Sericin, a waste product of the silk textile industry, has favorable physicochemical and biological properties. In this study, we extracted a low molecular weight (MW) sericin (LMW-sericin; below 10 kDa) by a performing high-temperature and high-pressure method and confirmed the MW using matrix-assisted laser desorption ionization-time of flight and liquid chromatography–mass spectrometry. Furthermore, we determined its biological effects on macrophages and human adipose stem cells (hASCs) as cell models to investigate the biocompatibility, immunomodulation behavior, and potential signaling pathway-related wound healing via analyses of gene expression of focal adhesion and human cytokines and chemokines using quantitative real-time polymerase chain reaction and cytokine assay. LMW-sericin showed good biocompatibility both in macrophages and hASCs. Macrophages cultured with 0.1 mg/ml LMW-sericin displayed an improved inflammatory response shown by the upregulation of CXCL9, IL12A, BMP7, and IL10, which developed Th1 and Th2 balance. LMW-sericin also improved the differentiation of macrophages toward the M2 phenotype by significantly enhancing the expression of Arg-1, which is conducive to the repair of the inflammatory environment. Moreover, the gene expression of hASCs showed that LMW-sericin promoted the secretion of beneficial adhesion molecules that potentially activate the gene transcription of differentiation and migration in hASCs, as well as significantly enhanced the levels of PKCβ1, RhoA, and RasGFR1 as fruitful molecules in wound healing. These findings provide insights into LMW-sericin application as a potential biomaterial for wound management.

Exceptional tumour responses to fasting-mimicking diet combined with standard anticancer therapies: A sub-analysis of the NCT03340935 trial

BackgroundCyclic fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as fasting-mimicking diets (FMDs), demonstrated additive or synergistic antitumour effects when combined with chemotherapy, targeted therapies, or immunotherapy in several preclinical in vivo models, including murine models of breast cancer, lung cancer, and colorectal cancer. However, no data on the antitumour efficacy of cyclic FMD in patients with cancer have been published so far. Here, we aim at reporting on patients with advanced cancer achieving complete and long-lasting tumour remissions with cyclic FMD in combination with standard anticancer therapies in the context of the phase Ib NCT03340935 trial. Patients and methodsThe NCT03340935 trial enrolled 101 patients with different tumour types, and it showed that a severely calorie-restricted FMD regimen is safe and feasible in patients with cancer receiving concomitant standard-of-care antineoplastic therapies. In addition, cyclic FMD resulted in positive metabolic and immunologic modifications, thus recapitulating the biological effects that in preclinical models were found to mediate the antitumour effects of fasting/FMD. ResultsOf the 101 patients enrolled in the NCT03340935 trial, we identified five patients with advanced, poor prognosis solid neoplasms (n = 1: extensive stage small cell lung cancer; n = 1: metastatic pancreatic adenocarcinoma; n = 1: metastatic colorectal cancer; n = 2: metastatic triple-negative breast cancer), who achieved complete and long-lasting tumour responses when treated with a combination of cyclic FMD and standard systemic treatments in the context of the NCT03340935 trial. ConclusionThese excellent responses prompt the initiation of clinical trials to investigate cyclic FMD in combination with standard antitumour therapies in specific clinical contexts.

S111: REPEATED INFUSIONS OF ESCALATING DOSES OF EXPANDED AND ACTIVATED AUTOLOGOUS NATURAL KILLER CELLS IN MINIMAL RESIDUAL DISEASE-POSITIVE PH+ ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS. A GIMEMA PHASE 1 TRIAL

Background: Due to age and co-morbidities, many Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are ineligible to undergo high-dose chemotherapy or allogeneic transplant as consolidation treatment. Our group reported the promising results of the chemo-free scheme D-ALBA based on dasatinib/blinatumomab in induction/consolidation, underlying the potential role of immunotherapy in this setting (Foà et al, NEJM 2020;383:1616-23). Considerable interest has been raised by natural killer (NK) cells. We developed a GMP protocol for NK cell ex vivo expansion in the presence of IL-2 and IL-15, and report the results of a phase 1 protocol of adoptive immunotherapy with activated and expanded autologous NK cells for Ph+ ALL patients in complete hematologic remission (CHR) but with persistent/recurrent minimal residual disease (MRD) ≥60 years or ineligible for other post-CHR treatment modalities. Aims: The primary endpoint was to determine the maximum tolerated dose of NK cells and the recommended dose for subsequent studies. Secondary endpoints were the assessment of safety and tolerability of the treatment, the immunologic modifications induced by the procedure and the clinical response to treatment. Methods: The planned 6 patients were enrolled: 5 in 1st CHR and 1 in 2nd CHR. Patients underwent repeated infusions (maximum 5) of escalating doses of NK cells, ranging from 1x106 to 5x107/kg of body weight (BW). No conditioning therapies were administered before the infusion; patients were allowed to continue tyrosine kinase inhibitors. Patients underwent a comprehensive MRD monitoring by Q-RT-PCR with a one-year follow-up. Immunophenotypic analysis on the NK cell product was performed before and after the expansion. Intracellular cytokine production and PBMC cytotoxic activity against K562 cells, allogeneic and autologous blasts were evaluated after expansion and at time 0 and 7 days from each NK cell infusion. Results: NK cells presented a 12.3-fold ex vivo expansion. Expanded cells showed an increased expression of activating receptors and measurable cytotoxicity against primary allogeneic and autologous blasts. One patient received a maximum NK cell dose of 5x106 cells/kg, 2 patients 1x107 cells/kg and 3 5x107 cells/kg/BW. No patient experienced infusion-related toxicities. Two adverse events were recorded (grade 1 and 2), both judged not treatment-related, that resolved after TKI suspension. The higher cell dose infusion resulted in a significantly increased expression of natural cytotoxicity receptors, a greater cytokine production by NK, T and NKT cells, and in an increased capacity of PBMC to lyse K562 cells. These modifications appear persistent over time. At a 1-year follow-up from the last infusion, 5/6 patients are alive in CHR (Table 1). The MRD levels reduced over time and 4/6 patients reached a complete molecular response (CMR) or a positive-not-quantifiable (PNQ) status during the study period. At a median follow-up of 30.8 months from the last infusion, the 5 patients who received the NK treatment in 1st CHR are still in CMR or PNQ, though 1 patient required additional treatment. The patient in 2nd CHR at the time of the infusions showed a rise in MRD and died of disease progression. Image:Summary/Conclusion: This phase 1 study demonstrates that autologous NK cells can be efficiently expanded ex vivo from MRD-positive Ph+ ALL patients in CHR. The infusion of these expanded cells is safe and induces a marked in vivo host immune response, suggesting that this approach represents a tolerable and feasible model worthy of being investigated in larger clinical studies.

Abstract 6161: HER3 expression is associated with cold tumor immune microenvironment and the regulation of its signal in humanized breast cancer patient derived xenograft models converts to hot tumor

Abstract Background: HER3 signal pathways in cancer cells are thought to be involved in up-regulation of PD-L1 expression, resulting in “cold” tumor immune microenvironment (TIME). However, little is known on the association of HER3 expression and immune related molecular network in breast cancer and the functional role of HER3 signals in antitumor immune responses. Methods: The dataset of the TCGA study was analyzed to determine the correlation of HER3 expression and antitumor immune molecules. Two breast cancer patient-derived xenograft (PDX) models were treated with patritumab (anti-HER3 antibody), polyclonal activated autologous T cells (PATCs) or a combination of patritumab and PATCs (P-PATCs) in order to test immunological modulation by the regulation of HER3 signals. RT-PCR, immunohistochemical staining and CyTOF were performed in tumors or liver tissue for CD3, CD4, CD8a, CD137, CD134/OX40, CD80, IFN-γ and PD-L1, LAG3, TIM3, FOXP3. In addition, HER3-knockdown human breast cancer cell lines and PBMC were co-cultured and comprehensive cytokine expression in supernatant was analyzed by bioplex. Results: In TCGA dataset analysis, HER3 expression was inversely corelated with expression of CD4, CD8A, IFN-γ, granzyme A/B. In humanized PDX models, although treatment of PATCs or patritumab alone showed limited anti-tumor effects, P-PATCs treatment showed a significantly greater anti-tumor response. Interestingly, the proportion of CD137 expressing T cell infiltration and mRNA expression of CD137 was significantly higher in P-PATCs group compared to patritumab or the PATCs group, while the proportion of CD4/8 T cell infiltration was also higher in the P-PATCs group. CyTOF revealed that the proportion of CD137 and CD134/OX40 expressing cells was higher in P-PATCs group compared to the PATCs group. In co-culture of PBMC with HER3 knockdown cancer cells, the secretion level of immune stimulatory factors (IL2, IFN-g, TNF-a) increased and immune inhibitors (IL6, IL10) decreases. Conclusions: These data suggest that HER3 expression in breast cancer associated with “cold” TIME and the regulation of its signal converts “cold” TIME to “hot”. Thus, inhibition of HER3 signal might be of interesting concept for both regulation of oncologic signal and immunological modulation in HER3-expressing breast cancer. Further HER3 related immune modulation exploration in breast cancer treatment strategy needs to be clarified in the future. Citation Format: Sunao Tanaka, Eiji Suzuki, Takeshi Kotake, Shinpei Kawaoka, Kosuke Kawaguchi, Tomomi Nishimura, Fengling Pu, Masakazu Toi. HER3 expression is associated with cold tumor immune microenvironment and the regulation of its signal in humanized breast cancer patient derived xenograft models converts to hot tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6161.

A phase 2 study of bevacizumab, erlotinib, and atezolizumab in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) associated or sporadic papillary renal cell cancer (pRCC).

TPS4604 Background: Papillary RCC accounts for 10-15% of kidney cancers and is the second most common subtype of RCC after clear cell RCC. HLRCC is a familial cancer syndrome characterized by a propensity for developing papillary kidney cancer. HLRCC-associated renal tumors are known to be clinically aggressive, with a paucity of treatment options. The combination of bevacizumab and erlotinib has shown promising activity in patients with HLRCC-associated RCC and sporadic pRCC (Srinivasan et al, ASCO 2020). We hypothesize that the addition of a PDL-1 inhibitor might provide synergistic clinical activity against these tumors. Methods: This is an ETCTN-sponsored, open-label, multicenter, phase 2 study evaluating bevacizumab, erlotinib and atezolizumab in adult and pediatric patients with advanced 1) HLRCC-associated RCC or 2) sporadic pRCC. Eligible patients will have cytologically or histologically confirmed advanced HLRCC- associated or sporadic pRCC, age ≥12 years, ECOG PS ≤2, no more than two prior regimens targeting the VEGF pathway, no prior treatment with PD-1 or PD-L1 inhibitors and adequate organ and marrow function. Patients with HLRCC-associated RCC or sporadic pRCC will be enrolled into parallel, independent cohorts. Initially, 12 adult patients with advanced HLRCC-associated RCC or sporadic pRCC will be enrolled into the safety run-in portion of the trial. If ≤ 3 dose-limiting toxicities are observed, enrollment will proceed into both cohorts and pediatric patients will be allowed to enroll. A Simon two-stage phase 2 minimax design will be used to determine accrual to each cohort. In the first stage, 12 evaluable patients will be enrolled into cohort 1) HLRCC-associated RCC or cohort 2) sporadic pRCC. If 0 of 12 patients have a CR, then no further patients will be enrolled in that cohort. If 1 or more of the first 12 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 21 evaluable patients (adult or pediatric) have been enrolled into each cohort for a total of 42 patients. Adult patients will receive a fixed dose of bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab (1,200 mg IV every 21 days) and erlotinib (150 mg PO daily). Pediatric patients will receive bevacizumab (15 mg/kg IV every 21 days) plus atezolizumab 15 mg/kg (max 1,200 mg IV every 21 days) and erlotinib 85 mg/m2 (max 150 mg PO daily). The primary endpoint is to assess the complete response rate according to RECIST 1.1 in patients with advanced 1) HLRCC-associated RCC and 2) sporadic pRCC. Secondary endpoints include safety and tolerability, objective response rate, disease control rate, progression-free survival and overall survival. Key exploratory endpoints include evaluation of immunologic modulation associated with this regimen. The study has just opened to accrual. Clinical trial information: NCT04981509.

Shrimp peptide hydrolysate modulates the immune response in cyclophosphamide immunosuppressed mice model.

Bioactive peptides are naturally found in various foods and were shown to have various distinct physiological as well as medicinal benefits. In this study shrimp peptide hydrolysate (SPH) was prepared to investigate its immunomodulatory effect against cyclophosphamide (CTX) induced immunosuppressed mice. The SPH effect was also analyzed on murine macrophage (RAW264.7 cells). The findings show that SPH stimulates macrophages to form multiple pseudopodia, has no cytotoxic effect, and increases phagocytic activity in RAW264.7 cells. Furthermore, the immunosuppressed in-vivo model illustrates the improvement in various aspects, that is body weight, escalation in immune organ index, and ameliorates histopathological transformation of thymus along with the spleen. SPH enhances cell-mediated immunity by facilitating splenocyte proliferation and inhibit excessive apoptosis. Moreover, the significant outcome had been observed with the upregulation of cytokines interferon-gamma (IFN-ϒ), interleukin-2 (IL-2) level and simultaneously downregulate certain genes include interleukin-4 (IL-4) and interleukin-10 (IL-10). Additionally, SPH expedites cellular immunity by enhancing the regulation of immunoglobulin A (IgA) and immunoglobulin M (IgM). However, these findings support the hypothesis that SPH is an effective immunomodulatory agent capable of preventing immune system hypofunction. It is necessary to investigate the detailed mechanism to rule out any unforeseen effects of SPH in future research. PRACTICAL APPLICATIONS: Chemotherapy medications, despite their dominating detrimental effects of damaging immunological organs such as the spleen and thymus, extend the treatment process as well as the destruction of the self-immune system. This study found that SPH is an effective immunomodulatory agent capable of avoiding immune organ hypofunction and improving cell mediate immunity by enhancing macrophage activation, phagocytosis, spleenocyte proliferation, suppressing apoptosis, and elevating cytokines and antibodies. As a result, SPH can be utilized as a nutritional and functional dietary supplement to boost immunological modulation in combination with chemotherapy medications in order to lessen their adverse effects.

In the Tumor Microenvironment, ETS1 Is an Oncogenic Immune Protein: An Integrative Pancancer Analysis.

Background Previous research suggested that ETS1 (ETS proto-oncogene 1, transcription factor) could be useful for cancer immunotherapy. The processes underlying its therapeutic potential, on the other hand, have yet to be thoroughly investigated. The purpose of this study was to look into the relationship between ETS1 expression and immunity. Methods TCGA and GEO provide raw data on 33 different cancers as well as GSE67501, GSE78220, and IMvigor210. In addition, we looked at ETS1's genetic changes, expression patterns, and survival studies. The linkages between ETS1 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of ETS1 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between ETS1 and immunotherapeutic response. Results ETS1 expression was shown to be high in tumor tissue. ETS1 overexpression is linked to a worse clinical outcome in individuals with overall survival. Immune cell infiltration, immunological modulators, and immunotherapeutic signs are all linked to ETS1. Overexpression of ETS1 is linked to immune-related pathways. However, no statistically significant link was found between ETS1 and immunotherapeutic response. Conclusions ETS1 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., KIRP, MESO, BLCA, KIRC, and THYM).

The potential role of eyestalk in the immunity of Litopenaeus vannamei to Vibrio parahaemolyticus infection II. From the perspective of long non-coding RNA

Long non-coding RNAs (lncRNAs) have been linked to immunological modulation. Unfortunately, little is known about the processes of immune control in shrimp. In crustaceans such as Litopenaeus vannamei, a prominent aquaculture species, the X-organ-sinus gland complex (XO-SG) in the eyestalk is an essential neuroendocrine regulatory organ. Eyestalk ablation is commonly employed in aquaculture to accelerate ovarian maturation in shrimp. It does, however, have a negative impact on the shrimps' immunocompetence and causes death. As a result, we used RNA-seq to profile the transcriptomes of L. vannamei hemocytes infected with Vibrio parahaemolyticus after the eyestalk ablation. Following strict transcript screening procedures, 2307 lncRNAs were identified from L. vannamei hemocytes in this study. Pearson correlation analysis was finally used to uncover 535 DElncRNAs and 1566 DEmRNA targets. According to the Venn diagram analysis, 326 non-eyestalk regulatory lncRNAs (NElncRNAs) with a target of 1014 non-eyestalk regulatory genes (NEmRNAs), 47 eyestalk negative regulatory lncRNAs (ENRlncRNAs) with a target of 95 eyestalk negative regulatory genes (ENRmRNAs), and 162 eyestalk positive regulatory lncRNAs (EPRlncRNAs) with a target of 457 eyestalk positive regulatory genes (EPRmRNAs) were screened. The bioinformatics analysis revealed that lncRNAs were associated with Axon regeneration, Rap1 signaling pathway, Thyroid hormone signaling pathway, TGF-beta signaling pathway, and PI3K-Akt signaling pathway, implying that lncRNAs may play a role in the regulation of the neuroendocrine-immune (NEI) system. Furthermore, several lncRNAs targeting HSP70, YWHAZ, FER2, HIF1α, and Notch were discovered and verified by qRT-PCR. These findings showed that regulation of lncRNAs in hemocytes which were controlled by the eyestalk might be one of the impact variables in controlling the differential expression of mRNAs associated with immune response in L. vannamei infected with V. parahaemolyticus.

The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer.

Post-translational modifications of proteins ensure optimized cellular processes, including proteostasis, regulated signaling, cell survival, and stress adaptation to maintain a balanced homeostatic state. Abnormal post-translational modifications are associated with cellular dysfunction and the occurrence of life-threatening diseases, such as cancer and neurodegenerative diseases. Therefore, some of the frequently seen protein modifications have been used as disease markers, while others are targeted for developing specific therapies. The ubiquitin and ubiquitin-like post-translational modifiers, namely, small ubiquitin-like modifier (SUMO) and neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8), share several features, such as protein structures, enzymatic cascades mediating the conjugation process, and targeted amino acid residues. Alterations in the regulatory mechanisms lead to aberrations in biological processes during tumorigenesis, including the regulation of tumor metabolism, immunological modulation of the tumor microenvironment, and cancer stem cell stemness, besides many more. Novel insights into ubiquitin and ubiquitin-like pathways involved in cancer biology reveal a potential interplay between ubiquitination, SUMOylation, and NEDDylation. This review outlines the current understandings of the regulatory mechanisms and assay capabilities of ubiquitination, SUMOylation, and NEDDylation. It will further highlight the role of ubiquitination, SUMOylation, and NEDDylation in tumorigenesis.

S100A8 as a Promising Biomarker and Oncogenic Immune Protein in the Tumor Microenvironment: An Integrative Pancancer Analysis.

Background S100 Calcium Binding Protein A8 (S100A8) is beneficial for cancer immunotherapy. However, the processes underlying its therapeutic potential have not been completely studied. Methods The Cancer Genome Atlas provides raw data on 33 different cancer types. GEO made available GSE67501, GSE78220, and IMvigor210. We investigated S100A8's genetic changes, expression patterns, and survival studies. The linkages between S100A8 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of S100A8 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between S100A8 and immunotherapeutic response. Results S100A8 expression was high in tumor tissue. The overexpression of S100A8 is associated with poor clinical outcome in patients with overall survival. S100A8 is associated with immune cell infiltration, immunological modulators, and immunotherapeutic indicators. S100A8 overexpression is connected to immune-related pathways. However, no statistically significant connection between S100A8 and immunotherapeutic response was identified. Conclusions S100A8 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., GBM, KIRC, LGG, and LIHC).

Rosacea, poor sleep quality, and obstructive sleep apnea: A commentary on potential interconnected features.

Although rosacea is classically considered a skin disorder, recent evidence shows that it is emerging as a systemic disease. The classical symptoms of burning, intense erythema, and flushing could be related to several systemic and metabolic comorbidities. We highlight the role of sleep disturbance as a possible trigger for rosacea, which could be explained by the inflammatory and stressful conditions that can be produced by poor sleep. In particular, we call attention to obstructive sleep apnea (OSA), a common multisystemic sleep disorder; it could be linked with rosacea in the context of the metabolic syndrome, which in turn is frequently associated with OSA. Obstructive sleep apnea may be accompanied by autonomic system activation and catecholamine release, which can aggravate rosacea. Poor sleep, resulting from any underlying cause, can have a range of effects including immunological modulation and intrinsic cutaneous changes (such as the impairment of skin barrier defense and modifications in the skin microbiome) that may trigger rosacea. Further studies on this subject could provide more evidence on these relationships and help to improve the patients' quality of life and management of this uncomfortable and potentially severe skin condition.

Atopic dermatitis: molecular, cellular, and clinical aspects.

Atopic dermatitis (AD) is a complicated, inflammatory skin disease, which numerous genetic and environmental factors play roles in its development. AD is categorized into different phenotypes and stages, although they are mostly similar in their pathophysiological aspects. Immune response alterations and structural distortions of the skin-barrier layer are evident in AD patients. Genetic makeup, lifestyle, and environment are also significantly involved in contextual factors. Genes involved in AD-susceptibility, including filaggrin and natural moisturizing, cause considerable structural modifications in the skin's lipid bilayer and cornified envelope. Additionally, the skin's decreased integrity and altered structure are accompanied by biochemical changes in the normal skin microflora's dysbiosis. The dynamic immunological responses, genetic susceptibilities, and structural modifications associated with AD's pathophysiology will be extensively discussed in this review, each according to the latest achievements and findings.

Immunological Modification of the Head and Neck Cancer Microenvironment by Short Chain Fatty Acids

Immunological Modification of the Head and Neck Cancer Microenvironment by Short Chain Fatty Acids