Spontaneous tumor regression mediated by human T cells in a humanized immune system mouse model

Abstract

Immunodeficient mice reconstituted with a human immune system (HIS mice) give rise to human T cells, which make them an attractive system to study human immune responses to tumors. However, such HIS mice typically exhibit sub-optimal responses to immune challenges as well as fail to develop antigen-specific B or T cell memory. Here we report HIS mice mediate spontaneous regression of human B cell lymphoma Raji. Tumor regression was dependent on CD4+ and CD8+ T cell responses and resulted in T cell memory. The T cell memory elicited was mainly Raji-specific, however some level of cross-protection was also elicited to a related B cell lymphoma cell line Ramos. Single-cell RNAseq analysis indicated activation of CD8+ T cells in regressing Raji tumors as well as clonal expansion of specific T cell receptors (TCRs). Cloning of TCRs from Raji-infiltrating T cells into a Jurkat reporter cell line showed reactivity specific for Raji tumor cells. Overall, we report a platform for studying in vivo human T cell tumor immunity by highlighting spontaneous Raji tumor regression, clonal TCR expansion, and T cell memory in HIS mice.

Human CD4 cytotoxic T lymphocytes mediate potent tumor control in humanized immune system mice

“…In support of this hypothesis, CD8 T cells in HIS mice have been shown required to control the growth of Raji, a B lymphoma cell line expressing high levels of co-stimulatory molecules (ref. 66 in press). These findings suggest that human immune cells exploit distinct mechanisms to target different tumors, and that CD4 abundance in the HIS model does not preclude CD8 T cell in clearing tumors.…”

“…HIS mice were generated by engrafting irradiated newborn or 4-week-old StRG mice with 5 × 10 4 to 1 × 10 5 human CD34 + HSPCs isolated from fetal liver or cord blood, respectively. Fetal liver CD34 + HSPC were obtained from Advanced Biosciences Resources (Alameda, CA) with proper consent 66 and cord blood CD34 + HSPC were obtained from AllCells, HemaCare, or STEMCELL Technologies. Human immune cell reconstitution was confirmed using flow cytometry 16-24 weeks after HSPC engraftment.…”

PD-L1 expression in testicular germ cell tumors undergoing spontaneous regression

“…Several theories have been proposed about the mechanisms of spontaneous regression, among which the most attention is given to an intense immune response and ischaemia as a result of hypoperfusion and high metabolic demands of the tumour tissue [23][24][25][26]. Historical examples of tumour regression following acquired infection highlight the importance of the inflammatory response in limiting tumour progression [23][27] Recent research on humanized mouse models confirms the active role of CD8+ and CD4+ lymphocytes in the spontaneous regression of allogeneic B cell lymphoma [28]. However, the variable response to immunotherapy with checkpoint inhibitors of different types of tumours, especially testicular germ cell tumours, points to multiple mechanisms of tumour regression, which does not depend exclusively on lymphocytic inflammation, as well as to the possible multiple roles of immune checkpoints and/or their ligands.…”