Urolithin A Induces T Memory Stem Cell Expansion and Antitumor Immunity

T cells play an important role in progression of colorectal cancer (CRC), but response to immune checkpoint blockade therapy in this disease is generally poor. Previous studies have indicated that mitophagy can enhance CD8⁺ T cell–dependent antitumor immunity; however, methods to induce mitophagy are not clinically available. Concentrated forms of Urolithin A (UA), a natural metabolite of ellagitannins found in pomegranate extract, induce mitophagy and attenuate inflammation in vivo, with UA-containing supplements having been approved as safe for humans. Thus, Denk and colleagues sought to investigate if UA-induced mitophagy can augment antitumor immunity and showed that UA upregulates major histocompatibility class I (MHC-I) on tumor cells and induces T memory stem cell (T_SCM) expansion and effective antitumor T-cell responses. Oral administration of UA to mice not only induced MHC-I expression and increased CD8⁺ T-cell infiltration, but also led to reduced tumor incidence and size. Similar results were observed in UA-treated organoids along with an increased sensitivity to PD-1 blockade. Additionally, investigation into the effects of UA on adoptive immunotherapy revealed an induction in the number of CD8⁺ T cells, less terminally exhausted CD8⁺ T cells, a greater T-cell memory phenotype, as well as greater tumor suppression. Mechanistically, Pink1-dependent mitophagy in T cells was induced by UA treatment, which supported mitochondrial release of protein phosphatase phosphoglycerate mutase family member 5 (PGAM5) and subsequent dephosphorylation of β-catenin, activation of Wnt signaling, and T_SCM formation, which together led to improved antitumor immunity. Furthermore, administration of UA also promoted T_SCM in humans as well as supported the expansion of potent chimeric antigen receptor T_SCM, which have previously been shown to have enhanced tumor killing capabilities. In summary, this work shows that UA induces antitumor CD8⁺ T-cell immunity and suggests that the use of UA in combination with immunotherapies, such as immune checkpoint blockade, can be beneficial.

Denk D, Petrocelli V, Conche C, Drachsler M, Ziegler PK, Braun A, et al. Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy. Immunity 2022;55:2059–73.e8.

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