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

Background Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect fl ect human-specific fi c aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined. fi ned. 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 fi ltration by endogenous human immune cells and immunocompetence of the model. Findings We found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), pex ), terminally exhausted (Tex ex-term) ) and tissue-resident (TRM) RM ) cells in tumour-bearing humanized mice with accumulation of T ex-term and TRMin RM in the tumour. In addition, we identified fi ed 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 fi c 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, fi ltration, correlating with control of human tumours. Interpretation We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined fi ned 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. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).