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Nature: Anti-tumor γδ T cells need oxygen to function.
Nature: Anti-tumor γδ T cells need oxygen to function. Brain tumors breathe more oxygen, leading to hypoxic microenvironment that damages the anti-tumor activity mediated by innate γδT cells.
Reduce the oxygen consumption of brain tumors or inhibit hypoxia-inducible factor-1α in γδ T cells to reactivate the tumor-killing activity of γδ T cells, leading to prolonged survival of mice bearing brain tumors.
Based on this, Park et al. published a paper entitled “Antitumor γδ T cells need oxygen to function” in the journal Nature Immunology, proving that the tumor killing activity mediated by γδ T cells is affected by hypoxia in the brain tumor microenvironment (TME) . The alleviation of hypoxia reactivates γδ T cells, leading to prolonged survival time.
γδT cells are innate immune cells that play a key role in immune surveillance, especially in the skin, lungs and intestines. According to their cytokine profile, γδ T cells can be roughly divided into IFN-γ producing γδ T cells and interleukin (IL)-17 producing γδ T cells.
IFN-γ-producing γδ T cells are considered to have anti-tumor activity, and IL-17-producing γδ T cells have recently been shown to promote tumor progression and metastasis. There are many clinical trials using ex vivo expanded γδ T cells from human peripheral blood as adoptive T cell therapy for cancer treatment. However, the clinical efficacy of adoptive γδ T cell therapy has not been consistently reported.
Here, Park and colleagues first used two publicly available data sets, the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), to reveal the relationship between adaptive CD4+ and CD8+ T cell infiltration and patient’s The overall survival rate was negatively correlated. Brain cancer.
This is in sharp contrast with other solid tumors. On the other hand, γδ T cell infiltration is positively correlated with the increased survival rate of brain cancer patients, especially in low-grade gliomas. Park et al. used a clinically relevant mouse model of high-grade glioma (HGG) brain cancer to show that both γδ T cells and CD8+ T cells in glioma TME showed a phenotype of reduced cytotoxicity.
Single-cell sequencing analysis using tumor-infiltrating γδ T cells showed that cytotoxic γδ T cells expressed high levels of transcription factor HIF-1α and apoptosis-related regulatory protein Bax. The infiltration of γδT cells in tumors is negatively correlated with the expression levels of HIF-1α and Bax. Surprisingly, the depletion of γδ T cells and the genetic defect of γδ T cells did not affect the survival of HGG mice. Nevertheless, the authors proposed that specific properties of brain TME, such as hypoxic conditions, may inhibit the anti-tumor effect of γδ T cells.
Next, immunosuppression is one of the physiological signs of TME. Hypoxia is also an important stressor in TME, which drives adaptation and enables tumors to establish immune escape mechanisms. In addition, hypoxic areas in tumors lead to long-lasting HIF signaling, which drives cancer development, invasion, and immunosuppression.
The authors show that brain tumors consume more oxygen than other types of cancer. Therefore, they tested the hypothesis that suppression of hypoxia would reverse the immunosuppressive phenotype in brain tumors. Metformin is a drug approved by the FDA for the treatment of diabetes-related complications.
Recent studies have shown that metformin also has a strong immunomodulatory effect on immune cells. In addition, metformin inhibits oxygen consumption in tumor cells.
The authors showed that HGG-bearing mice treated with metformin achieved significantly prolonged tumor-free survival, and its efficacy was dependent on γδ T cells, because the depletion or lack of γδ T cells completely eliminated the efficacy of metformin. In addition, there was a significant increase in γδ T cells in metformin-treated mice.
Finally, according to the oxygen level in the brain TME, anti-tumor γδ T cells have two opposite modes. Under hypoxic conditions, γδ T cells express high levels of HIF-1α, which may increase cAMP levels and activate PKA signaling, thereby reducing the expression of NKG2D. Therefore, the anti-tumor activity of γδ T cells is abolished.
On the contrary, after alleviating hypoxic conditions, these γδ T cells restore their tumor-killing activity by up-regulating the production of NKG2D, granzyme B and IFN-γ. They are also resistant to the induction of apoptosis, which facilitates their increased infiltration into TME.
It is worth noting that the effect of hypoxia on γδT cells is still controversial. Hypoxia seems to enhance the cytotoxicity of γδ T cells to breast cancer cells cultured under normoxia, while another report shows that hypoxia has the least effect on the effector function of γδ T cells.
In summary, allogeneic γδ T cell adoptive therapy has been widely used in clinical trials to treat glioblastoma, but the effect is limited. The authors showed that in the U87MG xenograft model, the combination of ex vivo expanded human γδ T cells from peripheral blood and metformin achieved approximately 75% tumor-free survival.
Similarly, the ex vivo expanded human γδ T cells pretreated with the HIF-1α inhibitor Cay10585 have comparable efficacy. In contrast, γδ T cells alone did not show any therapeutic efficacy. This is an exciting result with clear clinical significance.
Combining ex vivo expanded γδ T cells with metformin or HIF-1α inhibitor can enhance the tumor-killing activity of γδ T cells.
Anti-tumor γδ T cells need oxygen to function, doi.org/10.1038/s41590-021-00874-9
(source:internet, reference only)