Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

ACP1 y la asociación entre obesidad y diabetes tipo 2. Un estudio confirmatorio / ACP1 AND THE ASSOCIATION BETWEEN OBESITY AND TYPE 2 DIABETES . A CONFIRMATION STUDY

En un estudio previo sobre sujetos con enfermedades cardiovasculares (ECV) hemos observado que en los pacientes obesos con genotipo *B/*B en el gen ACP1, la proporción de pacientes con diabetes mellitus tipo 2 (DM2) es significativamente menor en comparación con pacientes con otros genotipos en el gen ACP1. En este trabajo hemos llevado a cabo un nuevo estudio en sujetos con DM2 sin ECV y en sujetos no diabéticos sin ECV. Hemos estudiado 277 sujetos con DM2 sin ECV y 137 sujetos sanos sin DM2 y sin ECV. Se obtuvo el consentimiento informado de estos sujetos para participar en el estudio que fue aprobado por el Departamento institucional respectivo. El genotipo presente en el gen ACP1 se determinó por análisis de ADN. Las pruebas estadísticas fueron realizadas con el programa SPSS. El genotipo *B/*B que está asociado con la mayor concentración de isoforma F ejerce un efecto protector sobre la susceptibilidad a la DM2 en sujetos obesos. Se observa una correlación negativa entre la concentración de la isoforma F y el índice de probabilidades para la susceptibilidad a la DT2 en sujetos obesos. La presente observación confirma la asociación previamente observada en sujetos con ECV haciendo improbable la posibilidad de un mero artefacto casual de muestreo. La expresión de las isoformas de ACP1 en el tejido adiposo a través de una acción sobre la proteína de unión a los lípidos de los adipocitos y el metabolismo de los lípidos puede ejercer un papel importante en la susceptibilidad a la DM2 en sujetos obesos.

In a previous study on subjects with cardiovascular diseases (CVD) we have observed that in obese patients with ACP1*B/*B genotype the proportion of those with type 2 diabetes (T2D) is significantly lower as compared to other ACP1 genotypes. We have now carried a new study in subjects with T2D without CVD and in non diabetic subjects without CVD. We have studied 277 subjects with T2D without CVD and 137 healthy subjects without T2D and without CVD. Iinformed consent was obtained from these subjects to participate to the study that was approved by the Council of Department. ACP1 genotype was determined by DNA analysis. Statistical tests were carried out by SPSS programs. ACP1*B/*B genotype which is associated with the highest concentration of F isoform exerts a protective effect on susceptibility to T2D in obese subjects. A negative correlation is observed between F isoform concentration and odds ratio for susceptibility to T2D in obese subjects The present observation confirms the association previously observed in subjects with CVD making unlikely the possibility of a mere sampling chance artifact. The expression of ACP1 isoforms in adipose tissue trough an action on adipocytes lipid binding protein and lipid metabolism may exert an important role in the susceptibility to T2D in obese subjects

p53 Codon 72 Genetic Polymorphism in Asthmatic Children: Evidence of Interaction With Acid Phosphatase Locus 1

Several lines of evidence are implicating an increased persistence of apoptotic cells in patients with asthma. This is largely due to a combination of inhibition, or defects in the apoptotic process and/or impaired apoptotic cell removal mechanisms. Among apoptosis-inducing genes, an important role is played by p53. In the present study, we have investigated the possible relationship between p53 codon 72 polymorphism and asthma and the interaction with ACP1, a genetic polymorphism involved in the susceptibility to allergic asthma. We studied 125 asthmatic children and 123 healthy subjects from the Caucasian population of Central Italy. p53 codon 72 and ACP1 polymorphisms were evaluated using a restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method. There is a statistically significant association between p53 codon 72 polymorphism and allergic asthma: Arg/Arg genotype is more represented in asthmatic patients than in controls (P=0.018). This association, however, is present in subjects with low ACP1 activity A/A and A/B only (P=0.023). The proportion of children with A/A and A/B genotype carrying Arg/Arg genotype is significantly high in asthmatic children than in controls (OR=1.941, 95% C.I. 1.042-3.628). Our finding could have important clinical implications since the subjects with A/A and A/B genotypes of ACP1 carrying Arg/Arg genotype are more susceptible to allergic asthma than Pro/Pro genotype.