◥Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression.See article by Hoffmann et al., p. 19

Both clinical observations and experimental data suggest that MIF plays a pivotal role in the progression of HNSCC.

TIGIT is an immune checkpoint inhibitor expressed by effector CD4 + and CD8 + T, NK cells and regulatory T-cells. Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT monoclonal antibodies (mAbs) has shown in vitro potential to restore T-cell functions and therapeutic efficacy in murine tumor models when combined with an anti-PD(L)-1 antibody. Here, we demonstrate for the first time, broader TIGIT expression than previously reported in healthy donors and cancer patients: being observed on  T-cells, particularly in CMVseropositive donors and on tumor cells from hematological malignancies such as cutaneous T -cell lymphoma. Quantification of TIGIT density revealed tumor-infiltrating Treg as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be broader than the previously described anti-PD(L)-1 like restoration of  T-cell function. In addition to  T-cell re-invigoration, CD155 also mediated inhibition in  T-cells, an immune population not previously described to be sensitive to TIGIT inhibition, and could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS884448). In PBMC from cancer patients, as well as TILs from mice, the higher TIGIT expression in Treg correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, ADCCenabling anti-TIGIT mAb had superior antitumor activity, that was depending on Fc receptor engagement. In addition, we induced direct killing of TIGIT-expressing tumor cells both in human patient material and animal models, demonstrating strong rational for therapeutic intervention in heme malignancies. These findings reveal broad therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.

Mice that are constitutively null for the zinc finger doublesex and mab-3 related (Dmrt) gene, Dmrt5/Dmrta2, show a variety of patterning abnormalities in the cerebral cortex, including the loss of the cortical hem, a powerful cortical signaling center. In conditional Dmrt5 gain of function and loss of function mouse models, we generated bidirectional changes in the neocortical area map without affecting the hem. Analysis indicated that DMRT5, independent of the hem, directs the rostral-to-caudal pattern of the neocortical area map. Thus, DMRT5 joins a small number of transcription factors shown to control directly area size and position in the neocortex. Dmrt5 deletion after hem formation also reduced hippocampal size and shifted the position of the neocortical/paleocortical boundary. Dmrt3, like Dmrt5, is expressed in a gradient across the cortical primordium. Mice lacking Dmrt3 show cortical patterning defects akin to but milder than those in Dmrt5 mutants, perhaps in part because Dmrt5 expression increases in the absence of Dmrt3. DMRT5 upregulates Dmrt3 expression and negatively regulates its own expression, which may stabilize the level of DMRT5. Together, our findings indicate that finely tuned levels of DMRT5, together with DMRT3, regulate patterning of the cerebral cortex.