Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathy

Preneoplastic lesions carry many of the antigenic targets found in cancer cells but often exhibit prolonged dormancy. Understanding how the host response to premalignancy is maintained and altered during malignant transformation is needed to prevent cancer. To understand the immune microenvironment in precursor monoclonal gammopathy of undetermined significance (MGUS) and myeloma. we analyzed bone marrow immune cells from 12 healthy donors and 26 patients with MGUS/myeloma by mass cytometry and concurrently profiled transcriptomes of 42,606 single immune cells from these bone marrow samples. Compared with age-matched healthy donors, memory T cells from both MGUS and myeloma patients exhibited greater terminal effector differentiation. However, memory T cells in MGUS show greater enrichment of stem-like TCF1/7(hi) cells. Clusters of T cells with stem-like and tissue residence genes were also found to be enriched in MGUS by single-cell transcriptome analysis. Early changes in both NK and myeloid cells were also observed in MGUS. Enrichment of stem-like T cells correlated with a distinct genomic profile of myeloid cells and levels of Dickkopf-1 in bone marrow plasma. These data describe the landscape of changes in both innate and adaptive immunity in premalignancy and suggest that attrition of the bone marrow-resident T cell compartment because of loss of stem-like cells may underlie toss of immune surveillance in myeloma.