Therapeutic targets and biomarkers of tumor immunotherapy:response versus non-response

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response.The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression.Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors.Represented by immune checkpoint blockade and adoptive cell transfer,tumor immunotherapy has seen tremendous success in the clinic,with the capability to induce long-term regression of some tumors that are refractory to all other treatments.Among them,immune checkpoint blocking therapy,represented by PD-1/PD-L1 inhibitors(nivolumab)and CTLA-4 inhibitors(ipilimumab),has shown encouraging therapeutic effects in the treatment of various malignant tumors,such as non-small cell lung cancer(NSCLC)and melanoma.In addition,with the advent of CAR-T,CAR-M and other novel immunotherapy methods,immunotherapy has entered a new era.At present,evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect.However,the overall clinical response rate of tumor immunotherapy still needs improvement,which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents.Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future.In this article,we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Objectives::To investigate the prevalence of ACADM pathogenic variants, c.985A>G and c.199T>C, for medium chain acyl CoA dehydrogenase deficiency (MCADD) in a healthy population in the southern region of Brazil. Methods::This was an observational cross-sectional study with a convenience sampling strategy. The participants were recruited from the blood bank of the Hospital de Clínicas of Porto Alegre, Brazil. A total of 1000 healthy individuals from the state of Rio Grande do Sul were included. Genotyping for the c.199T>C and c.985A>G variants was performed using real-time polymerase chain reaction (PCR) and the PCR-restriction fragment length polymorphism (RFLP) technique, respectively. Individuals considered heterozygous for c.985A>G were subjected to additional acylcarnitine profile analysis using tandem mass spectrometry. Carrier frequency was obtained by calculating the ratio of heterozygous individuals to the total number of individuals analyzed and reported with a 95% confidence interval. Allele and genotype frequencies were calculated based on the Hardy-Weinberg equilibrium.Results::The c.985A>G variant was detected as heterozygotes in three individuals (frequency of the heterozygous genotype = 1:333, allele frequency= 0.0015, minimum frequency of MCADD= 1:444,444) whose acylcarnitine profiles were within normal limits. The c.199T>C variant was not identified.Conclusions::Considering the small sample size and associated allelic heterogeneity with MCADD, these findings are believed to denote the rarity or underdiagnosis of MCADD in southern Brazil. This study provides evidence for the need for further investigation to ascertain the contribution of these diseases to child morbidity and mortality in the country.