Abstract: The application provides T cell gene expression signatures that can be used to predict T cell therapy outcomes.

Abstract: The application provides modified immune effector cells wherein the DNA (cytosine-5)-methyltransferase 3A (DNMT3A)-mediated de novo DNA methylation of the cell genome is inhibited, and STAT5 signaling pathway is activated. The application also provides related pharmaceutical compositions and the methods for generating such modified immune effector cells. The application further provides uses of such modified immune effector cells for treating diseases such as cancers, infectious diseases and autoimmune diseases.

Abstract: Provided herein are methods and compositions for determining T-cell differentiation by comparing the methylation status of T cells relative to a T cell methylation index and using this determination to identify or isolate populations of T cells having desired T cell multipotency. Further, the present methods and compositions can be used to monitor or treat symptoms of chronic infections, autoimmune diseases, and cancer.

Abstract: This disclosure relates to the genetic modification of DNMT3A gene in immune cells. In certain embodiments, the modified immune cells may be used in adoptive T cells therapies to enhance immune responses against cancer or chronic infections. In certain embodiments, the disclosure relates to deleting, changing, or inserting nucleotides within the DNMT3A gene in immune cells, e.g., human CD8 T cells, such that the DNMT3A gene product does not function for methylation. In certain embodiments, modification of the DNMT3A gene provides an improvement in antigen-specific T cells functions and/or an enhancement of the longevity of the cells.

Abstract: Provided herein are methods and compositions for modulating T-cell activity by incubating a CD8 T cell with a signal 3 cytokine, such as IL-12. Incubation of naïve CD8 T cells, particularly, with a signal 3 cytokine can acquire long-lived memory associated gene expression characteristic of the stem cell memory subset of CD8 T cells. Further, incubation with signal 3 cytokines can induce changes to the epigenetic profile of naïve CD8 T cells that are more characteristic of bona fide Tscm cells than in vitro generated cells using traditional differentiation protocols. On account of epigenetic profiles being preserved during in vivo homeostasis, signal 3 cytokines such as IL-12 can be used to engineer a T cell population with the desired epigenetic profile that maintains effector functions and proliferative capacity.

Abstract: This disclosure relates to the genetic modification of DNMT3A gene in immune cells. In certain embodiments, the modified immune cells may be used in adoptive T cells therapies to enhance immune responses against cancer or chronic infections. In certain embodiments, the disclosure relates to deleting, changing, or inserting nucleotides within the DNMT3A gene in immune cells, e.g., human CD8 T cells, such that the DNMT3A gene product does not function for methylation. In certain embodiments, modification of the DNMT3A gene provides an improvement in antigen-specific T cells functions and/or an enhancement of the longevity of the cells.

Abstract: Provided herein are methods and compositions for modulating T-cell activity by altering DNA methylation status. Altering the methylation status of CD8+ T cells can prevent T-cell exhaustion and maintain effector functions during sustained antigen exposure. The methods and compositions can be used to treat symptoms of chronic infections and cancer. Further, the methods and compositions relate to predicting T-cell activity by measuring the methylation status of specific memory cell methylation markers and using the markers to identify and separate populations of CD8 T cell having desired T cell activity. The memory cell methylation markers can further be used to identify subjects with chronic infections or cancer that would benefit from personalized therapy, including immune checkpoint blockade therapy.

Abstract: This disclosure relates to the genetic modification of DNMT3A gene in immune cells. In certain embodiments, the modified immune cells may be used in adoptive T cells therapies to enhance immune responses against cancer or chronic infections. In certain embodiments, the disclosure relates to deleting, changing, or inserting nucleotides within the DNMT3A gene in immune cells, e.g., human CD8 T cells, such that the DNMT3A gene product does not function for methylation. In certain embodiments, modification of the DNMT3A gene provides an improvement in antigen-specific T cells functions and/or an enhancement of the longevity of the cells.