Aberrant HSP90 Expression in Lymphocytes and HSP90 Response to Anti-PD-1 Therapy in Lymphoma Patients

Abstract

HSP90 family of molecular chaperones has been shown to be implicated in various stages of tumor growth and development. Recent studies have highlighted the role of extracellular HSP90 in tumor immunology, however, the role that HSP90 plays in the regulation of immune responses and the impact of cancer immunotherapy, including immune checkpoint blockade, on HSP90 is still unclear. Here we assessed the surface and intracellular expression of constitutive cytosolic HSP90β isoform, mitochondrial HSP90 homolog TRAP1 and co-chaperone STIP1/HOP in T, NK, B and NKT cells derived from peripheral blood and bone marrow samples of patients with Hodgkin and B-cell Non-Hodgkin lymphomas. HSP90β and STIP1 were overexpressed in B lymphocytes, while TRAP1 expression was decreased in T, B, NK and NKT cells of lymphoma patients. HSP90 overexpression in B cells was not associated with malignant B cell clones, since no clonotypic B cells were detected by immunoglobulin heavy chain (IgH) gene rearrangements. PD-1 blockade was found to differently affect the intracellular and surface HSP90 in T, B, NK and NKT cells in patients with relapsed or refractory classical Hodgkin lymphoma. Modulating HSP90 was found to affect the NK cell degranulation response and IFNγ production in lymphoma patients. These findings provide the rationale to further explore HSP90 homologs for improving patient response to cancer immunotherapy.

Impaired Heat Shock Protein Expression in Activated T Cells in B-Cell Lymphoma

“…HSPs play important roles in folding, degradation, and maturation of client proteins [ 5 , 6 ]. Dysregulated expression of various HSP members has been reported in various tumors, where high HSP expression is typically associated with an unfavorable clinical outcome [ 14 , 40 , 42 , 43 , 44 ]. Several studies have shown that HSP90 inhibitors downregulate surface PD-L1 expression and may also potentiate the effect of PD-1 and CTLA-4 treatments [ 39 ].…”

“…Several studies have shown that HSP90 inhibitors downregulate surface PD-L1 expression and may also potentiate the effect of PD-1 and CTLA-4 treatments [ 39 ]. In our previous study, we found that the PD-1 inhibitor (Nivolumab) affects HSP90 expression in peripheral blood and bone marrow lymphocytes in refractory or recurrent Hodgkin’s lymphoma patients [ 40 ].…”

“…In our previous study, we have shown that the PD-1 inhibitor Nivolumab affects the expression of HSPs in peripheral blood and bone marrow lymphocytes of BCL patients. However, the exact mechanism by which HSPs may modulate immune checkpoints remains unclear [ 40 ]. The aim of this study was to examine the expression of intracellular and extracellular HSPs during T cell activation and the effect of combined blockade of HSP90 and immune checkpoints on T cell functional activity in vitro.…”

Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy (Review)

“…Hsp90 inhibitors. Heat shock protein 90 (Hsp90) is an oncogene that promotes c-MYC mRNA stability (108), regulates tumour immunology (109) and participates in aberrant metabolism of lymphoma cells (110). Hsp90 inhibitors act as novel senolytic agents (111) that have rapidly developed in preclinical research on lymphomas.…”