Enhance anti-tumor CD8+ T cell function by inhibiting CD36

• Applicant: Dr. Guoliang Cui
• Subject Area: Immunology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420112816

The clinical success of immune checkpoint inhibitors has revealed the power of harnessing immune cells (such as CD8+ T cells) in the treatment of cancers. Currently available immunotherapies are very promising, but also have limitations. The therapeutic efficacy of these current immunotherapies is limited by the lack of enough CD8+ T cell infiltration into tumors and also the immunosuppressive property of tumor microenvironment. After infiltrating into tumor microenvironment, anti-tumor CD8+ and CD4+ T cells are usually functionally compromised and become “exhausted”, a phenomenon also observed in the T cells during chronic viral infections. On the other hand, exhausted T cells are also characterized by endogenous metabolic stress, such as mitochondrial dysfunction. We hypothesize that metabolic reprogramming of the exhausted T cells enhances the tumoricidal function. This hypothesis is supported by our preliminary data obtained from mouse melanoma models: 1) mouse melanoma tumor interstitial fluid had higher levels of fatty acids than blood 2) certain fatty acids suppressed CD8+ T cell glycolysis and effector function and 3) inhibiting fatty acid transportation proteins (such as CD36) enhanced glycolysis and promoted CD8+ T cell anti-tumor function. These data support the model that tumor development is associated with altered nutrient availability (in this case, it is fatty acids) for CD8+ T cells. This change in nutrient availability may impact anti-tumor and antiviral CD8+ T cell metabolism, energy production and survival. Based on the preliminary data, I propose the following research aims: (1) dissecting the underlying mechanisms through which CD36 regulates anti-tumor CD8+ T cell function and 2) examining if dual blockade of metabolic and immune checkpoints synergistically enhance CD8+ T cell responses to tumors. This study may present an entirely different perspective on anti-tumor CD8+ T cell immunity, and may lead to the development of novel therapies that stimulate CD8+ T cell responses by manipulating fatty acid metabolism.

• DFG Programme: Research Grants