The exquisite specificity, amplitude, and quality of T cells govern tumor initiation, progression, and 2 responses to therapy. Two of the most revolutionary and promising immunotherapies are the immune checkpoint 3 blockade and the adoptive cell transfer, which are both dependent on the robust engagement of cytotoxic T 4 effector (Teff) cells to control or eradicate cancer. A robust T cell-mediated anti-tumor response requires the 5 coordination of nutrient and energy supplies with Teff cell expansion and function. However, the high metabolic 6 demands of tumor cells compromise the function of Teff cells by competing for nutrients within the tumor micro- 7 environment (TME). We propose that the critical barrier, which limits the patient?s response to immunotherapy, 8 is the hostile metabolic microenvironment within tumors. We have previously shown that the transcription factors 9 c-Myc and HIF1? are differentially required for driving the central carbon metabolic programs during T cell acti- 10 vation and differentiation. We recently revealed that asparagine (Asn) is the most upregulated amino acid upon 11 T cell activation, and its bioavailability represents a key metabolic node that governs the central carbon metab- 12 olism and effector function in Teff cells. Some cancer cells solely rely on extracellular Asn to support growth and 13 proliferation, representing a metabolic vulnerability of cancer. However, Teff cells can maintain an intracellular 14 Asn pool for cell growth and function either through the uptake of extracellular Asn or through de novo biosyn- 15 thesis of Asn, indicating a layer of metabolic plasticity of T cells. Enforced restriction of extracellular Asn rewires 16 central carbon catabolic programs, leading to enhanced anti-tumor effector function in Teff cells. Moreover, these 17 Teff cells are characterized by an enhanced ATF4 and Nrf2 signaling response. Hence, we hypothesize that 18 modulation of Asn bioavailability can optimize carbon assimilation and integrate stress-response sig- 19 naling pathways, enabling a robust anti-tumor response in metabolically restricted tumor microenviron- 20 ments. To test our hypothesis, we propose to 1) decipher the reprogramming of central carbon metabolic path- 21 ways and assess the impact of key metabolic steps on Teff cells in the context of Asn restriction; 2) determine 22 the role of ATF4/Nrf2 axis in regulating the effector function of Teff cells; 3) target critical signaling and metabolic 23 nodes to engineer central carbon catabolic programs, thus enhancing function and persistence of Teff cells, and 24 4) develop and test strategies to simultaneously exploit Asn dependence as a cancer cell metabolic vulnerability 25 and maximize systemic anti-tumor immunity. Collectively, the completion of this project will reveal fundamental 26 principles of the emerging connections between the tumor?s microenvironment, cell metabolism, and anti-tumor 27 immunity. These studies are critical to developing novel approaches that improve clinical outcomes of cancer 28 immunotherapy substantially.
The efficacy of cancer immunotherapy is dependent upon the generation of robust anti-tumor T effector cells. Novel strategies are needed to enhance the metabolic fitness of T cells at the level of precise biochemical reaction, molecular interactions, amenable to pharmacologic manipulation. We postulate that the bioavailability and the biosynthetic process of asparagine determines T cell robustness and anti-tumor function. This proposal will enable us to develop novel metabolic modulations on anti-tumor T effector cells to improve the efficacy and broaden the therapeutic horizons of immunotherapy.