Nutrient Competition: A New Axis of Tumor Immunosuppression

Abstract

It is thought that cancer cells engage in Warburg metabolism to meet intrinsic biosynthetic requirements of cell growth and proliferation. Papers by Chang et al. and Ho et al. show that Warburg metabolism enables tumor cells to restrict glucose availability to T cells, suppressing anti-tumor immunity.

Figure 1.. Nutrient Competition between Tumor Cells and T Cells Controls Immune Function within Tumors

Schematic depicting glucose metabolism and cellular signaling In highly glycolytic progressor tumors and repressor tumors undergoing therapy. In the progressor tumor (left), constitutive activation of the Akt/mTOR pathway by PD-L1 expressed on tumor cells causes high levels of tumor cell glycolysis and absorption of extracellular glucose. Decreased extracellular glucose levels causes impaired glycolysis in T cells, wherein depletion of the glycolytic metabolite PEP causes unrestrained SERCA activity, sequestration of cytoplasmic Ca2⁺ into the ER and impairment of TCR-induced Ca2⁺ flux and effector function. In the regressor tumor (right), therapeutic anti-PD-L1 antibodies bind to PD-L1 causing its endocytosis and inactivation. Loss of constitutive PD-L1 signaling leads to decreased activation of the Akt-mTOR pathway decreased tumor cell glycolysis and increased extracellular glucose concentrations. Increased extracellular glucose drives T cell glycolysis, replenishing PEP levels, inhibiting SERCA-dependent sequestration of cytoplasmic Ca2⁺ and promoting TCR-induced Ca2⁺ flux and anti-tumor effector functions. Alternatively, constitutive overexpression of PCK1 in adoptively transferred T cells increases availability of PEP leading to inhibition of SERCA, increased anti-tumor effector function and tumor regression.