Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintu-itively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor -infiltrating CD8+ T cells and interferon y (IFNy) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and 0-catenin signaling. In animal models, T cell-derived IFNy promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated 0-catenin deacetylation and enhanced 0-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNy-PKM2-0-catenin axis prevents HPD in pre -clinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNy-PKM2-0-catenin cascade underlies ICB-associated HPD.

Automated summary

Immune checkpoint blockade can have durable responses against cancer, but some patients experience rapid cancer progression during immunotherapy. The mechanism behind how tumors accelerate their progression during immune checkpoint blockade is not well understood. In preclinical models, immune checkpoint blockade can cause hyperprogressive disease. Interestingly, patients with hyperprogressive disease but not complete response exhibit elevated levels of tumor fibroblast growth factor 2 and β-catenin signaling. T cell-derived interferon γ promotes tumor fibroblast growth factor 2 signaling, suppressing PKM2 activity and decreasing NAD+ levels, which leads to enhanced β-catenin acetylation and reprogramming of tumor stemness. Targeting the interferon γ-PKM2-β-catenin axis can prevent hyperprogressive disease in preclinical models. These findings demonstrate the importance of the crosstalk between immunogenic, metabolic, and oncogenic pathways in immune checkpoint blockade-associated hyperprogressive disease.