The Expression of CTLA-4 in Breast Tumors and Tumor-Infiltrating Leukocytes Affects Patients' Systemic Inflammatory Status and Varies According to Their Molecular Subtypes.

Recent evidence has pointed out that the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression is a poor prognosis factor. However, the implications of CTLA-4 expression on circulating inflammatory mediators are unclear for breast cancer. Tumor biopsies and blood samples were collected from 117 breast cancer patients. Oxidative stress parameters were evaluated in plasma samples by measuring the lipoperoxidation profile and nitric oxide metabolites (NOx). Interleukins 12 (IL-12) and 4 (IL-4) were assessed by ELISA. CTLA-4 expression was determined by immunofluorescence assessed by its labeling in tumor-infiltrating leukocytes (TILs) or breast tumors. Correlations between CTLA-4 expression in breast tumors with TCD4/TCD8 infiltrating lymphocyte and inflammation-related genes were performed using data from TIMER 2.0/TCGA databases (n = 2160). CTLA-4 expression in TILs significantly correlated to triple-negative breast tumors. Patients carrying CTLA-4-positive tumors exhibited lower plasmatic NOx levels, and those expressing CTLA-4 in TILs had reduced levels of IL-12 in plasma. No changes in either IL-4 or lipid peroxidation profiles were detected concerning any CTLA4 status. Compared to the Luminal A ones, oxidative stress parameters and cytokines were observed in patients bearing triple-negative tumors. CTLA-4 expression in all breast cancer subtypes positively correlated to TCD4/TCD8 lymphocyte infiltrates, as well as to the pro-inflammatory genes IL12A, IL4, NFKB1, NFKB2, NOS1, NOS2, and NOS3. CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, especially antitumor molecules such as IL-12 and NOx that correlate to more aggressive disease.

Cardiovascular toxicity following immune checkpoint inhibitors: A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials. METHODS: We conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: 57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3-5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06-1.73; p = 0.01). CONCLUSION: This meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.

Cytotoxic T Lymphocyte-associated Antigen 4 Polymorphisms Correlated with Graves' Disease in Patients of Han Ethnicity in Yunnan, China / Polimorfismos del antígeno 4 del linfocito T citotóxico correlacionados con la enfermedad de Graves en pacientes de la etnia Han en Yunnan, China

ABSTRACT Objective: To investigate the correlations between polymorphisms at position 49 in exon 1 and position 318 in the promoter of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene and autoimmune thyroid diseases in a Han Chinese population. Methods: Polymerase chain reaction-restriction fragment length polymorphism was utilized. The MseI and BbvI restriction endonucleases were used to detect and analyse position 49 in exon 1 and position 318 in the promoter as well as the T/C alleles of the CTLA-4 gene in peripheral blood samples from 112 patients with Graves' disease (GD), 101 with Hashimoto's thyroiditis (HT) and 100 healthy individuals. Results: At position 49 of exon 1, the frequencies of the GG genotype and the G allele in the GD group (χ2 = 12.147; p = 0.002) were statistically significantly higher than those in the control group (χ2 = 9.925; p = 0.002), while no statistically significant differences were found between the frequencies of the GG genotype and the G allele in the HT group (χ2 = 1.195; p = 0.550) and those in the control group (χ2 = 0.984; p = 0.321). No statistically significant differences in the promoter (−318) or the T/C alleles were observed among the three groups. Position 49 in the 17th codon of exon 1 of the CTLA-4 gene may be a candidate susceptibility marker in patients of Han ethnicity with GD. Conclusion: This finding helps us to better understand the genetic risks for GD and provides a direction for targeted gene therapy.

RESUMEN Objetivo: Investigar las correlaciones entre los polimorfismos en la posición 49 en el exón 1 y la posición 318 en el promotor del gen del antígeno 4 asociado al linfocito T citotóxico (CTLA-4), con las enfermedades autoinmunes de la tiroides en una población China de Han. Métodos: Se utilizó la reacción en cadena de la polimerasa-polimorfismo de la longitud de los fragmentos de restricción. Las endonucleasas de restricción de MseI y BbvI se utilizaron para detectar y analizar la posición 49 en el exón 1 y la posición 318 en el promotor, así como los alelos T/C del gen CTLA-4 en muestras de sangre periférica de 112 pacientes con enfermedad de Graves (EG), 101 con tiroiditis de Hashimoto (TH) y 100 individuos sanos. Resultados: En la posición 49 de exón 1, las frecuencias del genotipo GG y el alelo G en el grupo de EG (χ2 = 12.147; p = 0.002) fueron estadísticamente significativamente más altas que las del grupo de control (χ2 = 9.925; p = 0.002), pero no se encontraron diferencias estadísticamente significativas entre las frecuencias del genotipo GG y el alelo G en el grupo de TH (χ2 = 1.195; p = 0.550) y las del grupo de control (χ2 = 0.984; p = 0.321). No se observaron diferencias estadísticamente significativas en el promotor (−318) ni en los alelos T/C entre los tres grupos. La posición 49 en el codón17.° del exón 1 del gen CTLA-4 puede ser un marcador de susceptibilidad candidato en pacientes de la etnia Han con EG. Conclusión: Este hallazgo nos ayuda a comprender mejor los riesgos genéticos de la EG y ofrece una dirección para la terapia génica dirigida.

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo.

In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.