Friends Not Foes: CTLA-4 Blockade and mTOR Inhibition Cooperate during CD8+ T Cell Priming To Promote Memory Formation and Metabolic Readiness

Abstract

During primary Ag encounter, T cells receive numerous positive and negative signals that control their proliferation, function, and differentiation, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mammalian target of rapamycin inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti–CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mammalian target of rapamycin inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation, and an optimal metabolic program for CD8+ T cell memory.

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

“…It is known that blocking inhibitory receptors enhances T cell activation (Francisco et al, 2010; Keir et al, 2008), which might reflect that these treatments allow T cells to better compete for nutrients like glucose, allowing a greater engagement of glycolysis by TILs. Consistent with this idea and published reports (Parry et al, 2005; Pedicord et al, 2015; Staron et al, 2014), even treating in vitro activated T cells, which are already highly glycolytic, with PD-1 and CTLA-4 antibodies further slightly increased ECAR (Figures S3B, C). …”

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…These results contribute to a growing body of evidence that suggest mTOR inhibition can promote favourable immune effects. For instance, mTOR inhibitors have been shown to synergize with tumour vaccines, 41,42 in addition to αPD-L1 immune checkpoint blockade, 12 suggesting that combination of mTOR inhibitors and immune potentiating therapies could represent a broadly applicable therapeutic approach.…”

Feeding an army: The metabolism of T cells in activation, anergy, and exhaustion

“…There are some hints in recent studies to this reasoning. CTLA-4 signaling, for instance, has been shown to modulate metabolic signaling and inhibit the generation of mitochondrial reserve [58]. Studies of PD-1 signaling have revealed that it, too, can modify the metabolism of T cells.…”