Heat Shock Proteins in Lymphoma Immunotherapy

Abstract

Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.

Keywords: CAR NK; CAR T; checkpoint inhibitors; heat shock proteins; lymphoma.

Figure 1

Tumor microenvironment in cHL. HRS cells are surrounded by non-malignant immune and stromal cells. Inflammatory cells secrete cytokines, tumor necrosis family members (CD40L, CD30L) and other molecules (APRIL, BAFF) that bind to the proteins on the surface of HRS cells to promote growth and survival of HRS cells (1, 73). HRS cells express various markers of B cells, T cells, myeloid markers, markers of dendritic cells (74). HRS cells express PD-L1 to escape anti-tumor responses (75). HRS cells express Fas, but avoid FasL-mediated apoptosis by overexpressing c-FLIP (–77). HRS cells express FasL leading to apoptosis of Fas-expressing NK cells (76, 78). HSP chaperones and their corresponding co-chaperones are highly expressed in HRS cells, which further contribute to immunosuppressive TME (79, 80). HRS, Hodgkin and Reed-Sternberg cells; BCMA, B cell maturation antigen; APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor;PD-L1, programmed death ligand 1; PD-1, programmed death 1; CD30L, CD30 ligand; CD40L, CD40 ligand; CCL5, CC-chemokine ligand 5; IL-3R, interleukin-3 receptor; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand interactor; HSP, Heat shock protein; MSC, mesenchymal stromal cells; mBAFF, membrane-bound B-cell activating factor; MHC II, Major histocompatibility complex class II; HLA-E/G, Human leukocyte antigen- E/G; KIR2DL4, killer cell immunoglobulin-like receptor family member; c-FLIP, cellular FLICE-inhibitory protein; cHL, classic Hodgkin lymphoma; NK cells, natural killer cells.

Figure 2

HSPs and CAR T/NK cells in lymphoma immunotherapy. Chimeric Antigens Receptor (CAR) targeting CD19 and CD30 showed promising results in patients with r/r lymphoma (93, 129, 131, 132). Autologous NK cells pre-activated with cytokines (IL-2, IL-15) and 14-mer HSP70-derived peptide (TKD) can be used for ex vivo activation of NK cells for the adoptive transfer therapy (–140). Anti- HSP70 and HSP90 CARs were proposed for specific targeting of membrane-bound forms of HSP70 and HSP90 (134, 136).