CTLA4 blockade improved T-cell infiltration and function in glycolysis-low tumors.

  • Major Finding: CTLA4 blockade improved T-cell infiltration and function in glycolysis-low tumors.

  • Concept:In vivo, anti-CTLA4 had increased efficacy against tumors that had decreased tumor cell glycolysis.

  • Impact: Whether CTLA4 blockade is more effective in glycolysis-low tumors in humans warrants investigation.

Metabolic perturbation is characteristic of cancer, with increased glucose catabolism via glycolysis being a common feature. Because effector T cells also depend on glycolysis, their functions may be dysregulated in glycolysis-high tumors, potentially affecting the efficacy of immunotherapies. Zappasodi and colleagues investigated this using a mouse breast cancer model in which the tumors have high rates of glycolysis, finding that knocking down the gene encoding lactate dehydrogenase A (LDHA) to reduce tumor cell glycolysis led to increased tumor infiltration by immune cells, especially following CTLA4 blockade. Correspondingly, neoadjuvant anti-CTLA4 treatment increased survival in mice bearing Ldha-knockdown (glycolysis-low) but not wild-type (glycolysis-high) mammary tumors. Additionally, tumor-infiltrating CD4+ T cells in Ldha-knockdown tumors exhibited upregulation of IFNγ and TNFα, an effect that was particularly pronounced in regulatory T (Treg) cells. Further, increased IFNγ production by Treg cells was positively correlated with increased IFNγ production by cytotoxic CD8+ T cells in tumors. Finally, in vitro experiments showed that the abnormal Treg-cell function caused by CTLA4 blockade was dependent on glycolysis by the Treg cells along with CD28 signaling. Collectively, these results suggest that the efficacy of CTLA4 blockade is limited in tumors depleted of glucose via elevated tumor cell glycolysis because of poor immune infiltration due to this metabolic competition and the presence of highly stable and immunosuppressive Treg cells. In contrast, in glycolysis-low tumors, in which glucose is more abundant in the tumor microenvironment, intratumoral immune infiltration is increased and Treg cells forced to engage in glycolysis after anti-CTLA4 treatment lose their immunosuppressive function, effects that contribute to the development of long-lasting antitumor immune responses. These results suggest that an investigation of whether CTLA4 blockade is more effective in glycolysis-low tumors in humans or whether CTLA4 blockade synergizes with inhibitors of tumor glycolysis may be warranted.

Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021;591:652–8.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.