Great Adaptations: Mitochondrial Changes During Cancer Cell Stress

For cancer cells to survive during times of stress, they must inhibit programmed cell death while maintaining the necessary functional metabolic pathways. Specifically, the stress that is induced when cells are separated from the extracellular matrix (ECM) can trigger anoikis, a caspase-dependent form of cell death. Additionally, ECM detachment results in profound alterations to the metabolic flux of cells. Mitochondria function at the nexus of both cellular metabolism and cell death to determine whether a cell lives or dies during stress.
In addition to ECM detachment, cancer cells also face extrinsic stress from immune cells within the tumor microenvironment (TME). Cancer cells can evade the immune system through a variety of mechanisms including the dampening of the immune response by expressing programmed death-ligand 1 (PD-L1) to engage its receptor (PD-1) on immune cells. Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites within the TME. Here, we find that anti-PD-1 ICB-resistant cancer cells produce abundant amounts of the metabolite itaconate (ITA) due to enhanced levels of the enzyme aconitate decarboxylase (Acod1). We also find that while Acod1 low cells reduce their mitochondrial pool during ECM detachment, cells with high levels of Acod1 better maintain their mitochondria in detached conditions. Acod1 has an important role in the resistance to anti-PD-1, as decreasing Acod1 levels in anti-PD-1-resistant cancer cells can sensitize tumors to anti-PD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Taken together, these findings suggest that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.