Researchers led by Ludwig Lausanne’s Melita Irving and senior postdoc Romain Vuillefroy de Silly reported in a September paper in The EMBO Journal the many ways in which the acidity of the tumor microenvironment compromises the function of cytotoxic (CD8+) T cells, which are essential to the immune clearance of tumors. The researchers discovered that acidity compromises key biochemical pathways essential to the metabolic health of CD8+ T cells as well as their responsiveness to the critical growth factor interleukin-2 (IL2). On a functional level, under acidic conditions the T cells exhibited reduced proliferation as well as impaired cytokine secretion and ability to kill target cells. Exploring the underlying mechanisms, Melita, Romain and their colleagues detailed how signaling through mTORC1—a key driver of cell growth and metabolism —is diminished in T cells under acidic conditions. Acidity additionally depresses levels of the transcription factor c-Myc, a master regulator of cellular metabolism and proliferation, due to both a decrease in its expression and an increase in its degradation. The findings underscore the potential benefits of normalizing pH in tumors in conjunction with immunotherapeutic interventions to improve patient responses.
Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling
The EMBO Journal, 2024 September 16