ABSTRACT
The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.
Subject(s)
Antigen-Presenting Cells/metabolism , CD28 Antigens/metabolism , Immune Checkpoint Inhibitors/therapeutic use , Myeloid Cells/metabolism , Neoplasms/drug therapy , Stem Cell Niche/genetics , Humans , Immune Checkpoint Inhibitors/pharmacology , Neoplasms/immunologyABSTRACT
In the original version of this Article, the data for Mother ID 8; 13; 25; 31; and 47 of Table 2 was merged. This has now been corrected in both the PDF and HTML versions of the Article.
ABSTRACT
PURPOSE: With the description of circulating fetal DNA in maternal blood, noninvasive prenatal diagnostics became theoretically possible. As the presence of background maternal DNA interferes with the detection of fetal DNA, analytical methods require genetic markers capable of distinguishing by quantitative or targeted approaches the minor population of DNA molecules of the fetus. Here we evaluate the feasibility of analyzing fetal DNA with novel DIP-STR genetic markers, designed for the investigation of forensic mixed biological evidence. METHODS: The DIP-STR molecular approach is based on sequence-specific analysis of paternally inherited fetal alleles. These sequences are biallelic deletion/insertion polymorphisms (DIPs) located very close to short tandem repeat (STR) markers, for combined analysis. In this study, 48 women were tested with 28 DIP-STRs during the first, second, and third trimester of pregnancy. RESULTS: Positive results were obtained across markers, including longer ones (386 base-pairs) and with blood samples collected during early pregnancy, such as 10 weeks of gestational age. CONCLUSION: These data show that DIP-STR markers can be used to amplify specific genomic regions of circulating fetal DNA to obtain targeted genetic information. This method may contribute to developments in noninvasive prenatal paternity testing and diagnosis of certain genetic diseases.
Subject(s)
Cell-Free Nucleic Acids/analysis , Prenatal Diagnosis/methods , Alleles , Biomarkers/blood , Cell-Free Nucleic Acids/genetics , DNA/blood , Fathers , Female , Fetus , Forensic Genetics/methods , Gene Frequency/genetics , Genetic Markers/genetics , Genotype , Humans , INDEL Mutation/genetics , Microsatellite Repeats/genetics , Paternal Inheritance/genetics , Polymorphism, Genetic/genetics , Pregnancy , Sequence Analysis, DNA/methodsABSTRACT
Bio-geographic ancestry is an area of considerable interest in the medical genetics, anthropology and forensics. Although genome-wide panels are ideal as they provide dense genotyping data, small sets of ancestry informative marker provide a cost-effective way to investigate genetic ancestry and population structure. Here, we investigate the performance of a reduced marker set that combine different types of autosomal markers through haplotype analysis. In particular, recently described DIP-STR markers should offer the advantage of comprising both, low mutation rate Indels (DIPs), to study human history over longer time scale; and high mutation rate STRs, to trace relatively recent demographic events. In this study, we assessed the ability of an initial set of 23 DIP-STRs to distinguish major population groups using the HGDP-CEPH reference samples. The results obtained applying the STRUCTURE algorithm show that the discrimination capacity of the DIP-STRs is comparable to currently used small-scale ancestry informative markers by approaching seven major demographic groups. Yet, the DIP-STRs show an improved success rate in assigning individuals to populations of Europe and Middle East. These data show a remarkable ability of a preliminary set of 23 DIP-STR markers to infer major biogeographic origins. A novel set of DIP-STRs preselected to contain ancestry information should lead to further improvements.
