PD1 is expressed on exhausted T cells as well as virus specific memory CD8+ T cells in the bone marrow of myeloma patients

// Anne-Marit Sponaas 1 , Rui Yang 1 , Even Holth Rustad 1 , Therese Standal 1, 2 , Aud Solvang Thoresen 5 , Camilla Dao Vo 5 , Anders Waage 1, 3 , Tobias S. Slordahl 1, 3 , Magne Borset 1, 4 and Anders Sundan 1, 2 1 Department of Clinical and Molecular Medicine, Myeloma Research Center, Norwegian University of Science and Technology, Trondheim, Norway 2 Centre of Molecular Inflammation Research, Centre of Molecular Immune Regulation, Norwegian University of Science and Technology, Trondheim, Norway 3 Department of Hematology, St. Olavs University Hospital, Trondheim, Norway 4 Department of Immunology and Transfusion Medicine, St. Olavs University Hospital, Trondheim, Norway 5 Department of Medicine, Gjovik Hospital, Gjovik, Norway Correspondence to: Anne-Marit Sponaas, email: anne-marit.sponaas@ntnu.no Keywords: myeloma; bone marrow; checkpoint molecules; CD8 T cells; exhaustion Received: December 12, 2017     Accepted: July 20, 2018     Published: August 10, 2018 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 EOMES high Tbet low 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.