A hallmark cytokine associated with tumor-induced immunosuppression is TGF-β1. Although we detected increased circulation of TGF-β1 in tumor-bearing animals in some experiments, it did not exert an apparent inhibition on the autoimmune Teff cells at a distal site in healthy tissues. At cellular levels, Treg cells and MDSCs have long been recognized as critical mediators of immunosuppression in cancer. Our studies with self-antigen-specific T cells highlighted an increased

potency of these regulatory mechanisms in tumors versus healthy tissues. The molecular mechanisms responsible for the local immunosuppression remain to be elucidated. Possibly, a suppressive cytokine milieu, directly or indirectly related to Treg cells and MDSCs, inactivates Teff cells at the tumor site, which could be reactivated by an agonistic cytokine stimulation [40] or a global alteration of tumor gene expression profiles [41]. This study implicates CTLA4. Buparlisib order Suggestive of the intertwining between autoimmunity and antitumor immunity, protection from cancer is often associated with the same polymorphisms of the CTLA4 locus that are linked to autoimmune susceptibility [15, 18-20]. A conditional knockout model

established an essential role for CTLA4 in Treg cells Epacadostat [8]. Its intrinsic role in Teff cells has also been well-documented [9, 10]. Our study with a CTLA4 shRNA model indicates a distinction between quantitative variation in CTLA4 and the “all-or-nothing” model of CTLA4 knockouts. A subtle reduction of CTLA4 did not impair Treg-cell function, but substantially promoted Teff-cell capacity in tumor settings. An expansion of immunotherapy trials has generated a plethora of novel ideas in cancer immunology. The entangling of auto-immunity toxicity with antitumor benefit has provoked a shift of perspective whereby autoimmune side effects are considered

not only a welcome marker but actual effectors for antitumor immunity [7]. A direct comparison of about cancerous versus healthy tissue in interaction with self-antigen-specific Teff cells revealed their intrinsic potential in tumor eradication. However, they were subjected to regulatory mechanisms that have been evolved to induce tolerance to nonmalignant self-tissue, even more so in the tumor microenvironment. Therefore, self-antigen can be effectively targeted for antitumor immunity, but harnessing the tumor-destruction capacity of self-antigen-specific T cells requires effective strategies to overcome the suppressive microenvironment at the tumor site. CTLA4 blockade therapies can abrogate suppressive tumor milieu by reverting the local predominance of Treg cells over self-antigen-specific Teff cells. On the other hand, a subtle reduction of CTLA4 reflecting genetic variations may substantially alter an immunoprivileged environment evolved in a solid tumor through an intrinsic impact on Teff cells.