Abstract
BackgroundTumor employs various means to escape immunosurveillance and inhibit immune attack, and strategies have been developed to counteract the inhibitory signals. However, due to the complex suppressive mechanisms in the tumor microenvironment, blocking one or a few inhibitory signals has only limited effects on therapeutic efficacy. Instead of targeting tumor immunosuppression, we considered from another point of view, and hypothesized that manipulating T cells to make them resist any known or unknown suppressive mechanism may be more effective for cancer treatment.MethodsWe used OT-1 cells transduced with retroviruses encoding Akt and human peripheral blood lymphocytes (PBLs) transduced with retroviruses encoding both Akt and a chimeric antigen receptor (CAR) specific for tumor antigen EpCAM to examine the effect of over-expressing Akt on tumor specific T cells in tumor environment.ResultsWe show that Akt activity of T cells in the tumor environment was inhibited, and over-expressing Akt in OT-1 cells increased the cytokine production and cell proliferation in the presence of B16-OVA tumor cells. What’s more, adoptive transfer of OT-1 cells over-expressing Akt inhibited B16-OVA tumor growth and prolonged mouse survival. To examine if over-expressing Akt could increase the anti-tumor activity of T cells in human cancer, PBLs co-expressing EpCAM specific CAR and Akt were cultured with EpCAM-expressing human prostate cancer cells PC3M, and less inhibition on cell proliferation and less apoptosis were observed. In addition, adoptive transfer of PC3M specific T cells over-expressing Akt resulted in more dramatic tumor inhibitory effects in PC3M bearing NOD/SCID mice.ConclusionsThese data indicates that over-expressing Akt in tumor specific T cells increases T cell proliferation and activity in the tumor environment, and enhances anti-tumor effects of adoptively transferred T cells. Our study provides a new strategy to improve the efficacy of adoptive T cell therapy, and serves as an important foundation for clinical translation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1611-4) contains supplementary material, which is available to authorized users.
Highlights
Tumor employs various means to escape immunosurveillance and inhibit immune attack, and strategies have been developed to counteract the inhibitory signals
Akt expression in the T cells is down-regulated in the tumor microenvironment To verify that Akt activation in T cells is inhibited in tumor environment, T cells were isolated from OT-1 transgenic mice, stimulated with anti-CD3 and antiCD28 antibodies, and incubated with B16-OVA tumor culture medium supernatant. 24 h later, the levels of phosphorylated Akt were determined by western blot
To examine Akt activation state of T cells in tumor microenvironment in vivo, T cells were isolated from tumor draining lymph nodes (TDLN) and distant lymph nodes (LN) of B16-OVA tumor bearing mice, and Akt phosphorylation was detected
Summary
Tumor employs various means to escape immunosurveillance and inhibit immune attack, and strategies have been developed to counteract the inhibitory signals. Due to the complex suppressive mechanisms in the tumor microenvironment, blocking one or a few inhibitory signals has only limited effects on therapeutic efficacy. Instead of targeting tumor immunosuppression, we considered from another point of view, and hypothesized that manipulating T cells to make them resist any known or unknown suppressive mechanism may be more effective for cancer treatment. With deeper understanding of the interactions between tumor and immune system, therapeutic strategies have been developed to resist immunosuppression, such as using antibodies to block CTLA-4 or PD-1 signaling, inhibiting IDO activity, depleting regulatory T cells, etc. It’s easy to understand that, confronting such a complex immunosuppressive microenvironment, strategies targeting one or two inhibitory signals have only limited effects on therapeutic efficacy. Through analysis of T cell signaling pathways, we found that Akt is in the central node of immune modulation
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