T cells responsive to minor histocompatibility (H) antigens are extremely effective in curing leukemia but it remains unknown whether they can eradicate solid tumors. We report that injection of CD8(+) T cells primed against the immunodominant H7(a) minor H antigen can cure established melanomas in mice. Tumor rejection was initiated by preferential extravasation at the tumor site of interferon (IFN)-gamma-producing H7(a)-specific T cells. Intratumoral release of IFN-gamma had two crucial effects: inhibition of tumor angiogenesis and upregulation of major histocompatibility complex (MHC) class I expression on tumor cells. Despite ubiquitous expression of H7(a), dissemination of a few H7(a)-specific T cells in extralymphoid organs caused neither graft-versus-host disease (GVHD) nor vitiligo because host nonhematopoietic cells were protected by their low expression of MHC class I. Our preclinical model yields unique insights into how minor H antigen-based immunotherapy could be used to treat human solid tumors.

Adoptive transfer of allogeneic T cells has unmatched efficacy to eradicate leukemic cells. We therefore sought to evaluate in kinetic terms interactions between T cells and allogeneic leukemic cells. T cells primed against the model B6 dom1 minor histocompatibility antigen were adoptively transferred in irradiated B10 (B6 dom1 -positive) and congenic B10.H7 b (B6 dom1 -negative) recipients, some of which were also injected with EL4 leukemia/lymphoma cells (B6 dom1 -positive). A key finding was that the tissue distribution of the target epitope dramatically influenced the outcome of adoptive cancer immunotherapy. Widespread expression of B6 dom1 in B10 recipients induced apoptosis and dysfunction of antigenspecific T cells. Furthermore, in leukemic B10 and B10.H7 b hosts, a massive accumulation of effector/memory B6 dom1 -specific T cells was detected in the bone marrow, the main site of EL4 cell growth. The accumulation of effector/memory cells in recipient bone marrow was EL4 dependent, and its kinetics was different from that observed in recipient spleen. We conclude that strategies must be devised IntroductionT-cell immunosurveillance can prevent the development of several malignancies. Nevertheless, the common occurrence of neoplasia shows that cancer immunosurveillance is leaky. Not only are cancer cells commonly ignored by the immune system, they can induce anergy or deletion of tumor-reactive T cells. In addition, it has proven exceedingly difficult to elicit curative immune responses with tumor vaccines. 1,2 Several factors explain the disappointing results obtained in tumor vaccine trials: low immunogenicity of tumor-associated epitopes, absence of high-avidity tumorreactive T cells in the peripheral T-cell repertoire, location of cancer cells outside the secondary lymphoid organs, and microenvironmental features in the tumor cell stroma (physical barriers, cytokines) that hinder productive interactions between T cells and cancer cells. [3][4][5][6][7] Many drawbacks of tumor vaccines can be curtailed by the use of adoptive T-cell immunotherapy. 8 Indeed, the T-cell repertoire from an allogeneic donor comprises T lymphocytes that can recognize with high avidity non-self-epitopes expressed by recipient cancer cells. Furthermore, these T cells can be primed ex vivo against their target antigen before adoptive transfer. Injected cells can be self-major histocompatibility complex (MHC)-restricted T lymphocytes that recognize polymorphic MHC-associated peptides-that is, minor histocompatibility antigens (MiHA)-or they can be allo-MHC restricted. [9][10][11][12][13] Many clinical studies have shown that a single injection of allogeneic lymphocytes can eradicate up to 10 12 hematopoietic malignant cells. [14][15][16][17] The remarkable efficacy of adoptive T-cell immunotherapy in eradicating leukemia/lymphoma cells probably constitutes the most convincing evidence that T lymphocytes can cure established cancer. 15 Moreover, recent studies suggest that the efficacy of adoptive immunotherapy can be extended ...

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The THP‐1 cell line is broadly used as a model for acute myeloid leukemia (AML) with MLL fusion and to study monocyte differentiation and function. We studied THP‐1 cells obtained from two major biorepositories. The two cell lines were closely related with a percentage match of short tandem repeat (STR) profiles ranging from 93.75% to 100%, depending on the algorithm used. Nevertheless, we found that the two cell lines presented discordant HLA type, cytogenetic aberrations and AML‐related gene expression (including critical targets of MLL fusion). These discrepancies resulted mainly from loss of heterozygosity (LOH) involving five chromosomal regions. In view of their aberrant expression of key “leukemia” genes (e.g., LIN28B, MEIS1 and SPARC), we argue that one of the THP‐1 cell lines may not be a reliable model for studying leukemia. Their defective expression of HLA molecules and abnormal adhesion properties is also a caveat for studies of antigen presentation. In a more general perspective, our findings show that seemingly minor discrepancies in STR profiles among cell lines may be the sign of major genetic drift, of sufficient magnitude to affect the reliability of cell line‐based research.