Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in acute myeloid leukemia (AML) patients entering HCT with poor-risk features. 1-3 When HCT does produce prolonged relapse-free survival (RFS), it commonly reflects graft-versus-leukemia (GVL) effects mediated by donor T cells reactive with antigens on leukemic cells. 4 As graft T cells have not been selected for leukemia-specificity and frequently recognize proteins expressed by many normal host tissues, GVL is often accompanied by morbidity and mortality from graft-versus-host disease (GVHD). 5 Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens. 6 We therefore isolated a high

Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor–immune interfaces through defined T cell/antigen interactions. We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors. In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors. However, late relapses developed at 22 and 18 months, respectively. Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs. Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.

Summary: Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.

While T cell-based vaccines have the potential to provide protection against chronic virus infections, they also have the potential to generate immunopathology following subsequent virus infection. We develop a mathematical model to investigate the conditions under which T cells lead to protection versus adverse pathology. The model illustrates how the balance between virus clearance and immune exhaustion may be disrupted when vaccination generates intermediate numbers of specific CD8 T cells. Surprisingly, our model suggests that this adverse effect of vaccination is largely unaffected by the generation of mutant viruses that evade T cell recognition and cannot be avoided by simply increasing the quality (affinity) or diversity of the T cell response. These findings should be taken into account when developing vaccines against persistent infections.Vaccination expands the numbers of lymphocytes specific for a given pathogen. However, in some circumstances, increasing the number of antigen-specific lymphocytes may fail to provide protection and instead lead to an adverse outcome following exposure to the pathogen. Vaccine-induced pathology can occur for many reasons. For instance, the recent adenovirus 5-based vaccination against human immunodeficiency virus (HIV) led to an increased probability of infection following exposure (18). Alternatively, the severity of infection might increase, as seen with respiratory syncytial virus (RSV) following early attempts at immunization (10, 13, 14) and as potentially occurs with dengue virus, with which previous infection with one serotype may result in more severe pathology following challenge with heterologous serotypes (11,19). The problem of adverse effects is of current relevance in the context of the development of vaccines against persistent infections. Conventional techniques have not yielded effective vaccines, but a promising approach involves the generation of vaccines that induce T cell responses against such infections. In this paper, we use mathematical models to explore pathology following T cell-based immunization against persistent infections.Laboratory experiments with mice have demonstrated that increasing the number of specific lymphocytes can lead to increased pathology in chronic diseases, such as those caused by lymphocytic choriomeningitis virus (LCMV) and hepatitis B virus (HBV). HBV-transgenic mice, which are used as a model for chronic human HBV infection, develop acute liver failure due to loss of liver cells after adoptive transfer of HBV-specific CD8 T cells (8). In mice infected with chronic LCMV, the extent of immunopathology depends on the initial dose of virus and initial numbers of naive-phenotype-specific CD8 T cells (6,9,22). Since these experiments tested only narrow immune responses, a natural hypothesis was that the increased pathology might be avoided by broadening the immune response (22). However, predicting pathology requires understanding the complex interplay between virus replication, immune exhaustion, and immune escape.In th...