The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells

Abstract

Although natural killer (NK) cells are often described as first line defence against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing major histocompatibility complex class I chain-related molecule A (MICA) in a natural killer group 2 member D (NKG2D-) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD stimulation. When MICA and MICB expression was induced in human tumour cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumour cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumour cells.

Heat treatment increases the incidence of alopecia areata in the C3H/HeJ mouse model

“…HSPA (HSP70), in particular, may efficiently prime circulating T cells, evidenced by their promotion of DC function and, together with antigen, triggering autoimmune diseases such as diabetes mellitus (Milani et al 2002;Millar et al 2003). In addition, HSPA has been shown to induce the expression of NKG2D ligand MICA on DCs, and activate NK cells to kill target cells expressing MICA in an NKG2D-dependent manner (Elsner et al 2010). Furthermore, HSPA-augmented IFN-gamma release was abrogated by antibody against MICA (Qiao et al 2008).…”

Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients

“…26 Intriguingly, CRT exposure on malignant blasts also correlated with elevated amounts of circulating NK cells (Figure 3), perhaps reflecting the coexposure of HSP70 (which has previously been involved in clinically relevant antileukemia NK-cell responses). 35,36 Importantly, exposure of CRT, HSP70, and HSP90 on malignant blasts (which was not influenced by disease subtype) was associated with improved RFS and decreased odds for relapse on univariate (but not multivariate) Cox proportional hazard analysis ( Figure 5; Tables 2-3). These findings were corroborated by the association between high CALR mRNA levels and improved OS in 173 patients with AML from the public TCGA database (Figure 5), as well as by previous results linking CRT expression and/or exposure on neoplastic cells with improved disease outcome in patients with neuroblastoma, non-small cell lung carcinoma, colorectal carcinoma, and ovarian carcinoma.…”

Targeting Hsp70: A possible therapy for cancer

“…Moreover, Hsp70 interferes at various points on the apoptotic pathways, preventing stress from inappropriately inducing cell death. In addition to its anti-apoptotic function, Hsp70 has an immunomodulatory effect and shows cross presentation with the MHC-I molecule [14]. Hsp70 activates both arms of the immune system (innate and adaptive) and acts as a potent immunomodulator.…”