Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia

Abstract

Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8 cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8 T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by anti-gen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti-PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease. (Blood. 2010;116(14):2484-2493)

Autocrine Adenosine Signaling Promotes Regulatory T Cell–Mediated Renal Protection

“…27 Conversely, the interaction of Treg PD-1 with PD-L1 inhibits the proliferation of Tregs in the liver of patients with chronic hepatitis C virus infection. 28 This finding, in conjunction with our results and others demonstrating a requirement for PD-1 in Treg function, [23][24][25] suggests dual and opposing functions for Treg PD-1; inhibiting the activity of target immune cells and restricting the proliferation of Tregs to fine-tune local immune responses.…”

“…Analysis of highly pure PD-1 is a negative costimulatory molecule upregulated on activated effector T cells that inhibits T cell receptor signaling, 22 but recent studies have also demonstrated that PD-1 is essential for Tregs to suppress both CD4 and CD8 T cell responses. [23][24][25] In our study, PD-1 blockade completely reversed any protection offered by Tregs, even if the Tregs had been preincubated with an A 2A R agonist.…”

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

“…9 For example, usually inhibitory signaling via PD-1 is reported altered to stimulatory signaling in Treg found in environments rich in suppressive factors such as tumor microenvironments. 33,34 Our data suggest that the same mechanisms of "reverse" signaling apply to Breg.…”

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

“…15 T-cell suppression preventing excessive inflammatory response at the site of chronic inflammation depends on an intact PD-1/PD-L1 axis. 16 In the presence of activated T cells, in return, tumor cells upregulate PD-L1, the major mediator of immunosuppression, resulting in inhibition of T helper cell response and "T-cell exhaustion" via the PD-1 pathway. 4 Targeting the immune system as novel therapeutic modality has proven efficacy in CRC.…”