Dysproteinemias progress through a series of clonal evolution events in the tumor cell along with the development of a progressively more “permissive” immune tumor microenvironment (iTME). Novel multiparametric cytometry approaches, such as cytometry by time-of-flight (CyTOF) combined with novel gating algorithms can rapidly characterize previously unknown phenotypes in the iTME of tumors and better capture its heterogeneity. Here, we used a 33-marker CyTOF panel to characterize the iTME of dysproteinemia patients (MGUS, multiple myeloma—MM, smoldering MM, and AL amyloidosis) at diagnosis and after standard of care first line therapies (triplet induction chemotherapy and autologous stem cell transplant—ASCT). We identify novel subsets, some of which are unique to the iTME and absent from matched peripheral blood samples, with potential roles in tumor immunosurveillance as well as tumor immune escape. We find that AL amyloidosis has a distinct iTME compared to other dysproteinemias with higher myeloid and “innate-like” T cell subset infiltration. We show that T cell immune senescence might be implicated in disease pathogenesis in patients with trisomies. Finally, we demonstrate that the early post-ASCT period is associated with an increase of senescent and exhausted subsets, which might have implications for the rational selection of post-ASCT therapies.
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