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Abstract
Characterization of CD8+ T cells in the tumor microenvironment (TME) is important to predict responses to checkpoint therapy. The TME in multiple myeloma is the bone marrow, which also is an immune organ where immune responses are generated and memory cells stored. The presence of T cells with other specificities than the tumor in the bone marrow may affect the search for biomarkers to predict responses to immunotherapy in myeloma. Here, we found similar proportions of PD1+ CD8+ T cells and similar levels of PD1 expression on CD8+ T cells in the bone marrow of myeloma patients and healthy controls. PD1 expression on CD8+ T cells did not correlate with tumor load suggesting that at least some of the PD1+ CD8+ T cells were specific for non-myeloma antigens. Indeed, PD1+ EBV-specific CD8+ T cells were detected it the bone marrow of patients. Terminal effectors (Teff), effector memory (Tem) and central memory (Tcm) cells as well as exhausted T cells were all found in the myeloma bone marrow. However, myeloma patients had more terminal effectors and fewer memory cells than healthy controls suggesting that the tumor generate an immune response against myeloma cells in the bone marrow. The presence of CD8 EOMEShigh Tbetlow T cells with intermediate levels of PD1 in myeloma patients suggests that T cell types, that are known to be responsive to checkpoint therapy, are found at the tumor site.
Highlights
Anti-PD1 treatment has been effective in clinical trials of several advanced hematological and solid cancers [1, 2]
If one assumes that antigens from myeloma cells are responsible for activation of T cells and the subsequent upregulation of PD1 in tumorreactive CD8+ T cells, there should be either more PD1+ cells or higher levels of PD1 on the CD8+ T cells from myeloma patients compared to healthy controls
We set out to determine PD1 expression on CD8+ T cells in bone marrow aspirate from a cohort of myeloma patients and healthy controls enrolled in the Norwegian Myeloma Biobank Study/Biobank1 (The clinical information of the patients is shown in Supplementary Table 1 and the gating strategy in Supplementary Figure 1A)
Summary
Anti-PD1 treatment has been effective in clinical trials of several advanced hematological and solid cancers [1, 2]. The rationale behind anti-PD1 treatment is to abrogate the exhausted state of the patient’s tumor specific CD8+ T and NK cell responses This appears to be the case in animal studies and recently reported to be the case in clinical studies [12, 13], it is not entirely clear what happens in patients treated with checkpoint inhibitors. We found that a large proportion of the bone marrow PD1+ CD8+ T cells were T effector or T memory cells These PD1+ CD8+ T cells failed to degranulate in the presence of autologous myeloma cells and PD1 antibody, suggesting specificity to non- tumor antigens. This was supported by the presence of PD1+, EBV-specific T cells in the bone marrow of patients
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