Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy.

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

T helper 1 and 2 immune responses in relationship to pregnancy, nonpregnancy, recurrent spontaneous abortions and infertility of repeated implantation failures.

It is becoming clear that during each developmental stage of pregnancy, different immunological conditions exist and may even be necessary for success. The widely accepted T helper (Th) 1 and 2 concept has some limitations if applied to the various developmental stages of pregnancy. During the implantation period, a multidirectional cytokine network is necessary with the blastocyst producing cytokines and other factors and the endometrium synthesizing factors necessary for the embryonic development. Improper immune responses and an unbalanced cytokine network may be related to implantation failures, pregnancy losses and obstetrical complications. A propensity to Th1 immune responses has been reported in these conditions systemically or locally. The presence of elevated Th1:Th2 cell ratios, high concentration of Th1 cytokines secreted by peripheral blood mononuclear cells, elevated NK cell cytotoxicity and levels, and emergence of various autoantibodies are the supporting evidence. The underlying immunopathology for the preponderance of Th1 is unknown. Genetic, environmental, and hormonal etiologies need to be explored further in the future. The purpose of this review is to give an overview of what is known about the immune response in women with reproductive failures and provide an update of some of the most recent findings in this field.