Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor - PubMed (original) (raw)
Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor
Adam T Waickman et al. Cancer Immunol Immunother. 2012 Jun.
Abstract
The A(2A) adenosine receptor plays a critical and non-redundant role in suppressing inflammation at sites of hypoxia and tissue damage. The tumor microenvironment has high levels of adenosine as a result of hypoxia and ectopic expression of enzymes responsible for the generation of extracellular adenosine. Thus, we sought to determine the ability of A(2A) receptor null mice to immunologically reject tumors. We observed that mice lacking the A(2A) adenosine receptor showed significantly delayed growth of lymphoma cells when compared to WT mice. Furthermore, when immunized with a low dose of tumor or with an irradiated GM-CSF-secreting tumor vaccine, A(2A) receptor null mice showed significantly enhanced protection from a subsequent high-dose challenge from both immunogenic and poorly immunogenic tumor lines. This increase in protection was accompanied by an increase in the number of tumor-antigen-specific CD8 T cells at the vaccine-site draining lymph node. Finally, we found that A(2A) receptor null mice displayed more robust anti-tumor responses than WT mice when they were treated with a soluble B7-DC/Fc fusion protein designed to antagonize B7-H1-mediated co-inhibition. This combinatorial immunotherapy strategy could also be recapitulated with pharmacological A(2A) receptor blockade paired with B7-DC/Fc administration. In light of these data, we believe that blockade of the A(2A) adenosine receptor is an attractive target for tumor immunotherapy that synergizes with other immunomodulatory approaches currently in clinical trials.
Conflict of interest statement
Jonathan Powell is a Scientific Founder of Amplimmune, Inc.
Figures
Fig. 1
Decreased rate of tumor growth observed in mice lacking the A2A adenosine receptor. C57Bl/6 WT and A2A KO mice were injected s.c. with 106 luciferase expressing EL4 cells. Growth of the tumor was monitored by anesthetization, followed by i.p. injection with 1.5 mg of luciferin-K + salt and imaging with a IVIS system. a A2A KO mice showed significantly reduced rate of tumor growth compared to WT controls. b Detailed view of day 26 post-inoculation. c Time course of EL4-luciferase tumor growth. *P < 0.05
Fig. 2
A2A KO mice are protected from lethal tumor challenge by previous low-dose tumor. Inoculation WT and A2A KO mice were immunized s.c. with 103 EL4 cells, a dose that both genotypes easily rejected, and were allowed to rest for 60 days. After this period, all immunized mice, along with age-matched naive controls, were challenged with a normally lethal s.c. dose of 106 EL4 cells. The duration of tumor-free survival was recorded, along with the average tumor volume once growth was detected. a A2A KO mice receiving a low-dose tumor immunization showed increased rates of overall survival compared to either immunized WT mice or naive controls of either genotype, and b decreased rate of tumor growth
Fig. 3
A2A KO mice show an increased response to a tumor vaccine compared to WT mice. C57Bl/6 WT and A2A KO mice were immunized with a s.c. injection of 5 × 105 irradiated OVA-expressing EL4 cells mixed with 5 × 105 irradiated GM-CSF producing B16 cells. Eight days after immunization, the draining lymph nodes from the injection site were harvested and stained with a MHC Class I OVA tetramer and anti-CD8 antibody to enumerate the number of OVA-specific CD8 T cells. Significantly more OVA-specific CD8 T cells were found in the draining LNs of A2A KO mice, compared to WT controls. *P < 0.05
Fig. 4
Immunization with an irradiated GM-CSF–secreting melanoma line shows increased efficacy in mice lacking the A2A adenosine receptor. WT and A2A KO mice were immunized with 106 GM-CSF-secreting B16 melanoma cells s.c. and rested for 50 days. Immunized mice and naive age-matched controls were injected i.v. with 106 B16 cells and their lungs harvested after 16 days. After fixation in Fekete’s Solution, B16 nodules were counted under a dissecting microscope. a Images of dissected lungs following fixation. b Immunized A2A KO mice had significantly lower loads of countable B16 metastases than immunized WT mice, or either naive control. c weights of harvested lungs. *P < 0.05, **P < 0.001, ***P < 0.0001
Fig. 5
Treatment with soluble B7-DC/Fc fusion protein synergizes with the loss of A2A adenosine receptor signaling to enhance tumor rejection. WT and A2A KO mice were injected s.c. with 106 EL4 cells and injected i.p. on day 1, and every 3 days following for the duration of the experiment, with 100 μg B7-DC/FC or control IgG. a A2A KO mice receiving PD1 blockade by B7-DC/FC treatment showed significantly enhanced duration of tumor-free survival following inoculation compared to B7-DC/FC treat WT mice, or either IgG-treated control. b B7-DC/FC-treated A2A KO mice had a longer rate of overall survival compared to B7-DC/FC-treated WT mice, or either IgG-treated controls. c Combination of pharmacological A2A receptor blockade and B7-DC/Fc treatment results in reduced tumor growth. * P < 0.05 unpaired t test
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