Genomic and Immunologic Correlates in Prostate Cancer with High Expression of KLK2.

The identification of surfaceome proteins is a main goal in cancer research to design antibody-based therapeutic strategies. T cell engagers based on KLK2, a kallikrein specifically expressed in prostate cancer (PRAD), are currently in early clinical development. Using genomic information from different sources, we evaluated the immune microenvironment and genomic profile of prostate tumors with high expression of KLK2. KLK2 was specifically expressed in PRAD but it was not significant associated with Gleason score. Additionally, KLK2 expression did not associate with the presence of any immune cell population and T cell activating markers. A mild correlation between the high expression of KLK2 and the deletion of TMPRSS2 was identified. KLK2 expression associated with high levels of surface proteins linked with a detrimental response to immune checkpoint inhibitors (ICIs) including CHRNA2, FAM174B, OR51E2, TSPAN1, PTPRN2, and the non-surface protein TRPM4. However, no association of these genes with an outcome in PRAD was observed. Finally, the expression of these genes in PRAD did not associate with an outcome in PRAD and any immune populations. We describe the immunologic microenvironment on PRAD tumors with a high expression of KLK2, including a gene signature linked with an inert immune microenvironment, that predicts the response to ICIs in other tumor types. Strategies targeting KLK2 with T cell engagers or antibody-drug conjugates will define whether T cell mobilization or antigen release and stimulation of immune cell death are sufficient effects to induce clinical activity.

Immune Signature Linked to COVID-19 Severity: A SARS-Score for Personalized Medicine.

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical outcome for hospitalized patients remains a major challenge. Immunophenotyping and transcriptomic analysis of hospitalized COVID-19 patients at admission allow identifying the two categories of patients. Inflammation, high neutrophil activation, dysfunctional monocytic response and a strongly impaired adaptive immune response was observed in patients who will experience the more severe form of the disease. This observation was validated in an independent cohort of patients. Using in silico analysis on drug signature database, we identify differential therapeutics that specifically correspond to each group of patients. From this signature, we propose a score-the SARS-Score-composed of easily quantifiable biomarkers, to classify hospitalized patients upon arrival to adapt treatment according to their immune profile.

Prognostic value of immunological profile based on CD8+ and FoxP3+ T lymphocytes in the peritumoral and intratumoral subsites for renal cell carcinoma.

PURPOSE: We aimed to assess an "Immunological Profile (IP)" including CD8+ and FoxP3+ T lymphocytes for renal cell carcinoma (RCC) to evaluate its effects on tumor pathological characteristics, disease progression, and survival. METHODS: Adjacent normal and intratumoral specimens from 42 patients who had undergone radical nephrectomy for RCC were analyzed for counts of CD8+ and FoxP3+ T lymphocytes by immunohistochemistry. Tissue from both sites were evaluated and scored separately according to low (0) or high (1) expression of CD8 and FoxP3. A total score (min: 0, max: 4) was assigned to each patient. Thereafter, patients were divided into two groups for clinicopathologic and survival stratification based on score (IPWeak 0-2; and IPStrong 3-4). Survival curves were constructed using the Kaplan-Meier method, and a multivariable Cox regression model was used for overall survival (OS) and progression-free survival (PFS). RESULTS: The mean follow-up was 54.73 ± 21.34 months. Poor RCC characteristics including pT3-T4, tumor necrosis, lymphovascular invasion, lymph node involvement, and larger tumor size were significantly more common in the IPWeak patients compared to IPStrong (p < 0.05). Kaplan-Meier analysis showed that IPWeak patients had worse OS (62.5 vs. 100%; p = 0.006) and PFS (50 vs. 94.4%; p = 0.002) compared to IPStrong patients. In multivariable analysis, IPWeak (HR 8.64; 95% CI 1.09-68.05, p = 0.042) and high tumor node metastasis stage (HR 45.33; 95% CI 4.69-437.68, p < 0.001) were significant independent predictors of poor PFS. CONCLUSION: Assessment of IP including CD8+ and FoxP3+ T lymphocytes in adjacent normal and intratumoral sites in RCC may serve as a good predictive marker for PFS.

Gestational Diabetes and T-cell (Th1/Th2/Th17/Treg) Immune Profile.

BACKGROUND/AIM: Gestational diabetes mellitus (GDM) is a common pregnancy complication, characterized by insulin resistance and low-grade systemic inflammation with a pro-inflammatory immune system response. Our objective was to study the peripheral Th1, Th2, Th17 and Treg response in GDM compared to normal pregnancy. MATERIALS AND METHODS: Th1, Th2, Th17 and Treg subsets was determined by flow cytometry based on staining for specific intracellular cytokines, as well as C-reactive protein (CRP) and total IgE circulating levels. The health status of all offspring was also assessed 6 months post-delivery. RESULTS: A total of 49 Caucasian adult pregnant women were enrolled into a GDM (n=26) and Control (n=23) group. At the third trimester of pregnancy, the GDM group had a higher proportion of Th2, Th17 and Treg cells compared to control. Contrary to the control group, the GDM group exhibited no significant change in the Th1/Th2/Th17/Treg profile postpartum. Furthermore, higher circulating CRP and total IgE levels were noted in the GDM group compared to controls. At the 6-month post-delivery assessment, 30.8% of the offspring from the GDM group were found to have developed atopic dermatitis, food allergy or allergic proctocolitis compared to none from the control group. CONCLUSION: Compared to an uncomplicated pregnancy, GDM exhibits a significantly different peripheral T-cell profile at the third pregnancy trimester characterized by higher proportion of Th2, Th17 and Treg cells which persist six months post-delivery, while the increased high sensitivity CRP (hsCRP) levels stressed the low-grade inflammatory profile of this disease.

[The detection of proteomic markers and immunologic profile and their relationship with metabolic parameters in patients with gout.]

The actual concept of gout comprises both traditional metabolic theory of disorder of purine metabolism and external medium impact and involvement of immune inflammatory, genetic and proteomic factors. The proteomic study of patients with tofus gout and patients with asymptomatic hyperiricosuria was carried out using technique of fluid chromatography with mass-spectrometry and immunologic profiling. The specific proteomic markers of gout such as circulating interleukin-8 (IL-8)/CXCL8 and associated heterodimeric complex of myeloid-bound proteins MRP8/MRP14 (kalgranulin A/B) were established. The positive correlation was established concerning shifting of metabolic indices - components of lipid spectrum and level of uric acid both in patients with tofus gout and in lesser degree in patients with asymptomatic hyperiricosuria. It is proposed to consider biomarkers IL-8 and MRP8/MRP14 as independent predictor of development of metabolic shifting and cardiovascular pathology in patients with gout.