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Simple Summary: Despite the recent advancement in the treatment of ovarian cancer, it continues to be a largely incurable disease, plagued by de novo and acquired resistance to standard chemotherapeutics and novel second-line therapeutics. Therefore, identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have demonstrated that low Caspase-8 expression correlates with poor prognosis in ovarian cancer patients. Moreover, the lack of Caspase-8 alters transcriptional regulation in ovarian cancer cells. In Caspase-8 knockout cells, increased BRD4 expression, increased CDK9 activity, and resistance to Carboplatin and Paclitaxel were observed. We have also shown that combining BRD4 inhibitors with Carboplatin, Paclitaxel, and CDK9 inhibitors synergistically sensitized these cells to undergo cell death. Ovarian cancer is one of the most lethal gynecological cancers worldwide, with approximately 70% of cases diagnosed in advanced stages. This late diagnosis results from the absence of early warning symptoms and is associated with an unfavorable prognosis. A standard treatment entails a combination of primary chemotherapy with platinum and taxane agents. Tumor recurrence following first-line chemotherapy with Carboplatin and Paclitaxel is detected in 80% of advanced ovarian cancer patients, with disease relapse occurring within 2 years of initial treatment. Platinum-resistant ovarian cancer is one of the biggest challenges in treating patients. Second-line treatments involve PARP or VEGF inhibitors. Identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have determined that low Caspase-8 expression in ovarian cancer patients leads to poor prognosis. High-Grade Serous Ovarian Cancer (HGSOC) cells lacking Caspase-8 expression showed an altered composition of the RNA Polymerase II-containing transcriptional elongation complex leading to increased transcriptional activity. Caspase-8 knockout cells display increased BRD4 expression and CDK9 activity and reduced sensitivities to Carboplatin and Paclitaxel. Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel—combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance—BRD4 and pCDK9. [ABSTRACT FROM AUTHOR]

T-cell activation is a complex process involving a network of kinases and downstream molecular scaffolds or adaptors that integrate surface signals with effector functions. One key immune-specific adaptor is Src kinase-associated phosphoprotein 1 (SKAP1), which is also known as src kinase-associated protein of 55 kDa (SKAP55). This mini-review explains how SKAP1 plays multiple roles in regulating integrin activation, the "stop-signal", and the optimization of the cell cycling of proliferating T cells through interactions with various mediators, including the Polo-like kinase 1 (PLK1). Ongoing research on SKAP1 and its binding partners will likely provide important insights into the regulation of immune function and have implications for the development of new treatments for disease states such as cancer and autoimmunity. [ABSTRACT FROM AUTHOR]

CEACAM1 functions as a novel heterophilic ligand for TIM-3 and is necessary for TIM-3-mediated tolerance, which has marked consequences for inflammation, infection and cancer. Interaction of CEACAM1 and TIM-3 T cell regulation is mediated by a number of inhibitory cell surface molecules such as T-cell immunoglobulin domain and mucin domain-3 (TIM-3), a possible target for cancer immunotherapy that has been reported to act as an immune checkpoint in tumour-induced immune suppression. However, the tolerance inducing ligand for TIM-3 has yet to be uncovered, and TIM-3 may also possess activating functions under some circumstances. This study identifies carcinoembryonic antigen cell adhesion molecule 1 (CAECAM1) as the heterophilic ligand for murine TIM-3 that is required for TIM-3 to mediate tolerance and ensure its optimal maturation, cell surface expression and regulatory function. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses, with improved elimination of tumours in mouse colorectal cancer models. T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers.sup.1,2,3,4,5. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition.sup.6,7,8,9,10. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity., Author(s): Yu-Hwa Huang [sup.1] , Chen Zhu [sup.2] , Yasuyuki Kondo [sup.1] , Ana C. Anderson [sup.2] , Amit Gandhi [sup.1] , Andrew Russell [sup.3] , Stephanie K. Dougan [sup.4] [...]

Author(s): Yu-Hwa Huang; Chen Zhu; Yasuyuki Kondo; Ana C. Anderson; Amit Gandhi; Andrew Russell; Stephanie K. Dougan; Britt-Sabina Petersen; Espen Melum; Thomas Pertel; Kiera L. Clayton; Monika Raab; Qiang Chen; [...]

The protein kinases p56Lck and p59Fyn are capable of phosphorylating the costimulatory antigen (CD28) and can cause a three to eight fold increase in the subunit p85 of phosphatidylinositol kinase (PI) 3-kinase and the binding of protein tyrosine kinase, ITK to CD28 is regulated by p56Lck. The regulation of CD28 signaling probably defines the role of Src kinases in T-cell activation.

Anti-CD3 and anti-Fyn immunoprecipitates have PI 3-kinase activity as evaluated by TLC and HPLC. Free and receptor-bound Src-related tyrosine kinase p59fyn(T) bound to the lipid kinase. A unique process of interaction with PI 3-kinase has been evolved by Src-related kinases. PI-3 primarily bound to the SH3 region of Fyn. PI 3-kinase is a target of SH3 regions and probably will significantly influence the signals obtained from the T-cell antigen receptor zeta/CD3-p59fyn complex, because Fyn SH3 directly bound to the p85 subunit of PI 3-kinase, and an enhancement in the identification of Fyn SH3-related PI3-kinase activity is caused by anti-CD3 crosslinking.