(A) Functional unresponsiveness of TILs in the tumor milieu may have different mutually non-exclusive causes: (i) Ligation of PD-1 on T cells by tumor expressed PD-L1 may cause recruitment of phosphatase SHP2 and subsequent dephosphorylation of the TCR proximal signal transmitter Lck as well as attenuation of AKT-signaling. attack but also may harm tumor cells directly by interfering with oncogenic survival pathways. Together, DGK-inhibitors have very promising characteristics and may be beneficially included into the armamentarium of cancer immunotherapeutics. which express high levels of CTLA-4 constitutively. Activated T cells migrate into the tumor milieu where they engage with tumor cells expressing peptide-MHC that can be recognized by the T cell receptor (TCR). TCR-pMHC conversation will activate tumor cell killing processes unless suppression occurs through concomitant CVT 6883 PD-1/PD-L1 conversation. Killing of tumor cells can occur if the unfavorable signaling is usually blocked through anti-PD-1 or anti-PD-L1 antibodies. NK cells can recognize tumor cells that express low or no MHC and, thus, cooperate with CTL to prevent tumor escape. If tumor cell killing occurs, antigen is usually released which can be taken up by immature DCs. Immature DCs can mature to mature DCs which then present antigen to T cells in the lymph node, leading to the generation of new tumor-reactive T cells. If the natural process of antigen presentation does not occur (efficiently), therapeutic vaccination using generated antigen-loaded DCs or peptides may be applied. While vaccination has yet to yield measurable clinical response (van der Burg et al., 2016), high and often long-lasting response rates are achieved with adoptive TIL therapy (Rosenberg and Restifo, 2015) and CD19-directed CAR-T cell therapy (Fesnak et al., 2016; Park et al., 2016). Yet, despite its high promises, adoptive T-cell therapy still faces significant hurdles to become one of the mainstay cancer therapies: TIL therapy is limited to tumor entities from which sufficient TILs can be procured [mainly melanoma and renal cell cancer (RCC)] and TCR- or CAR-T-cell therapy requires the knowledge of tumor-specific antigens to which T cells can be safely directed without harming vital organs. Currently, CAR-therapy is restricted to leukemia and lymphoma that express CD19 as targetable antigens. Treatment of solid tumors is explored, such as glioblastoma expressing a mutant form of the epidermal growth factor (EGFRvIII) or adenocarcinoma expressing cancer-associated glycoforms of mucin (Newick et al., 2016; Posey et al., 2016). Moreover, safety issues need to be resolved since serious adverse effects have been reported in TCR- and CAR-therapy trials (Gross and Eshhar, 2016). Contrasting the currently limited application of adoptive T-cell CVT 6883 therapy, immunotherapy with checkpoint blockade antibodies has achieved exciting results across a wide variety of cancer entities, not limited to commonly assumed immunogenic tumors such as melanoma or RCC, but also in lung cancer, bladder cancer or head and neck cancer. Three checkpoint blockade antibodies are currently in the clinic. One targets the cytotoxic T-lymphocyte-associated protein (CTLA)-4 (Postow et al., 2015; Sharma and Allison, 2015), which is an intrinsic negative regulator of T-cell activation during T-cell priming. The other two antibodies target the programmed death (PD) pathway through binding to the PD-1 protein or its ligand PD-L1. The PD-1/PD-L1 checkpoint is an extrinsic off signal that is operative in peripheral tissues turning off T-cell function to help control local inflammatory responses and maintain self-tolerance. Impressive durable responses have been observed using anti-CTLA-4 and anti-PD-1 resulting in their approval for the treatment of several cancers (Callahan et al., 2016). Yet, it CVT 6883 has to be recognized that, overall, only a minority of patients experience substantial clinical benefit (around 15C40% depending on the tumor entity) (Sunshine and Taube, 2015; Ribas and Hu-Lieskovan, 2016). Improvements are necessary to unleash the full potential of immunotherapy and to potentially offer benefit to patients whose tumors are refractory to current therapies. Diacylglycerol kinase alpha: a checkpoint that negatively regulates T-cell function and curbs the activity of CD8-T and NK cells in the tumor microenvironment T cells, in particular TH1/TC1-polarized lymphocytes, are important players in the antitumor response. Not only is their abundance associated with good prognosis in many tumor types (Fridman et al., 2012), they are also required for therapeutic response to checkpoint blockade SLC2A2 therapy (Herbst et al., 2014; Tumeh et al., 2014). NK cells are innate cytotoxic lymphocytes appreciated for their ability to lyse virally infected cells as well as tumors. They play a complementary role to CD8-T cells as they recognize tumors which are resistant to T-cell killing due to downregulation or loss of MHC-class I molecules (refs. in Prinz et al., 2014). In some tumor types, such as RCC, they appear to play a prominent role as their number is predictive of good prognosis while that of CD8-T cells is not (Nakano et al., 2001; Eckl et al., 2012). While the value of the natural immune infiltrate in tumors is appreciated, it has to be recognized that the natural immune response is not sufficient to control tumor progression in most cases. Various mechanisms are known that contribute to tumor immune escape ranging from ignorance to active suppression (Frey and Monu,.