Human effector CD8⁺T cells with an exhausted-like phenotype control tumor growthin vivoin a humanized tumor model

Abstract

The functional relevance of CD8+ T cell phenotypes in human cancer is not well established. In preclinical studies, murine CD8+ T cells exhibiting an exhausted-like phenotype have been described to have drastically decreased anticancer activity while non-exhausted TCF-1+ progenitor CD8+ T cells have been thought to be mainly responsible for driving protective antitumor responses. However, human data has mostly been correlative by nature. By establishing a novel autologous humanized mouse tumor model, we found a CD8+ dominated T cell expansion upon tumor challenge and identified tumor-reactive CD8+ T cells through expression of CD137. This subpopulation of de novo arising human CD8+ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of exhaustion markers like PD-1, CD39 and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137+CD8+ T cells exhibited tumor-specific clonal expansion and presented signature overlap with tumor-reactive CD8+ T cells described in human cancer. We demonstrate superior anticancer activity of this exhausted-like human CD8+ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumors. Mice adoptively transferred with CD137+CD8+ T cells showed reduced tumor growth, higher CD8+ T cell persistence as well as tumor infiltration, correlating with control of human tumors. In summary, defined effective anticancer activity of human effector CD8+ T cells with an exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.