Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction

TIGIT predominantly regulates the immune response via regulatory T cells

“…Instead, our data suggest that TIGIT signaling induces a molecular program in Tregs that in turn drives the development of a dysfunctional phenotype in CD8 + T cells. This observation is in line with our previous study showing that the dysfunctional phenotype of CD8 + TILs is diminished after Treg depletion (25) and with a recent study showing that Tregs modify the tumor microenvironment to promote CD8 + T cell dysfunction (31). Similarly, Tregs have recently been shown to play an important role in the maintenance of T cell dysfunction in chronic LCMV infection (32).…”

Cytokine-induced killer cell therapy for modulating regulatory T cells in patients with non-small cell lung cancer

“…CD4 + CD25 + FOXP3 + Tregs account for 5-10% of all T lymphocytes in healthy individuals (23). Evidence suggests that Tregs contribute to immune suppression by dampening the antitumor immunity elicited by CD4 + T cells, CD8 + T cells, dendritic and NK cells (24)(25)(26)(27). Treg accumulations in tumors and peripheral blood have been linked to unfavorable disease outcomes of tumor invasion, recurrence and shortened survival for many human solid tumors, including hepatocellular carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, cervical cancer, NSCLC and breast cancer (28)(29)(30)(31)(32)(33).…”

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

“…In previous live-imaging studies, we and others have shown that effector CD8 T cells, shortly after TME entry, are found in an arrested motility state, in association with marginating myeloid APC populations (4,7,11,12). We previously demonstrated that the myeloid APC populations that engage incoming CTLs in vivo also mediate a stable synaptic contact with CTLs in vitro, a contact that induced calcium transients within the T cells that were equivalent to those produced by stimulatory APCs (4).…”

“…Such expansion is also presumed to precede establishment of TILs in human cancer, since T cells that bear tumor antigen-specific T cell receptors (TCRs) are vastly overrepresented within the tumor and indeed within the blood of afflicted individuals (9,10). With the exception of some ectopic models in which TMEs may be different than those in tumors that form more naturally, adoptive transfer and subsequent clonal expansion of T cells are insufficient to mediate tumor clearance (11)(12)(13). Similarly, adoption of high numbers of expanded and activated T cells in human patients is ultimately only sporadically successful as a monotherapy (13).…”