Human effector CD8+ T cells with an activated and exhausted-like phenotype control tumour growth in vivo in a humanized tumour model.

Abstract

Background: Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.

Methods: We established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.

Findings: We found human T cell subsets described in human cancer, including progenitor exhausted (T_pex), terminally exhausted (T_ex-term) and tissue-resident (T_RM) cells in tumour-bearing humanized mice with accumulation of T_ex-term and T_RM in the tumour. In addition, we identified tumour-reactive CD8⁺ T cells through expression of CD137. This subpopulation of de novo arising human CD137⁺ CD8⁺ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137⁺ CD8⁺ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8⁺ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8⁺ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137⁺ CD8⁺ T cells showed reduced tumour growth and higher CD8⁺ T cell tumour infiltration, correlating with control of human tumours.

Interpretation: We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8⁺ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.

Funding: Swiss Cancer Research foundation.