Tumor-Specific CD8+T Cells from the Bone Marrow Resist Exhaustion and Exhibit Increased Persistence in Tumor-Bearing Hosts as Compared to Tumor Infiltrating Lymphocytes

Abstract

AbstractImmunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor infiltrating lymphocytes (TILs) with significant clinical results. Despite these successes, the limitations of the current strategies are also emerging and novel approaches are needed. The bone marrow (BM) is an immunological niche that houses T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies. Herein, we demonstrate that T cells from the BM appear superior to TILs as a source of cells for cellular therapy. Specifically, they possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. Taken together, these data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.Key MessagesWhat is already known on this topicTIL therapy shows efficacy but significant limitations. T cell quality is an important determinant of responses to cellular immunotherapy.What this study addsT cells from the BM appear superior to TILs in phenotype, transcriptional profile, and function. These differences appear driven by tissue (e.g., bone marrow as compared to tumor).How this study might affect research, practice or policyThe BM could serve as an alternative source of cells for adoptive cellular therapy for solid tumors.