Human effector CD8+T cells with an exhausted-like phenotype control tumor growthin vivoin a humanized tumor model
Authors: Mietz Juliane , Kaulfuss Meike , Egli Lukas , Opitz Lennart , Münz Christian , Chijioke Obinna 
Published: October 2023

AbstractBackgroundHumanized tumor models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumor and immune system of human cancer. However, endogenous antitumor immunity in humanized models is still largely undefined.MethodsWe established a novel autologous humanized mouse tumor model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumors generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumors after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.FindingsWe found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), terminally exhausted (Tex-term) and tissue-resident (TRM) cells in tumor-bearing humanized mice with accumulation of Tex-termand TRMin the tumor. In addition, we identified tumor-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 asPRF1,GZMHandNKG7. 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 and higher CD8+T cell tumor infiltration, correlating with control of human tumors.InterpretationWe established an immunocompetent humanized tumor model, providing a tool for immunotherapy research and 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.FundingSwiss Cancer Research foundation.Research in contextEvidence before this studyAntitumor immune responses and outcome of immunotherapeutic interventions are not always consistent between mouse models of cancer and data available in humans. This may be due to species-specific differences, therefore models with a potential for better translatability are needed, such as humanized mouse models. However, there is limited data on human antitumor T cell immunity in humanized mice.Added value of this studyIn this study, we established an immunocompetent humanized tumor model that recapitulates hallmarks of human antitumor T cell responses, offering the possibility for further translational investigation of the interface between human tumors and endogenous anticancer immunity. Furthermore, using functionalin vitroassays and adoptive transfer, our study demonstrates the key importance of human effector CD8+T cells with an activated and exhausted-like phenotype in the antitumor immune response.Implications of all the available evidenceThe autologous humanized tumor model provided in this study can serve as a tool to elucidate human-specific immune features. By bridging a gap between syngeneic mouse tumor models and human-specific antitumor immune responses, the model may help open up avenues for greater translatability of preclinical data. Our findings suggest that exhausted-like effector CD8+T cells can be harnessed for clinical development of adoptive T cell therapies.