CD3- large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells

Abstract

Traditionally, heat shock proteins (HSPs) are believed to be located intracellularly, where they perform a variety of chaperoning functions. Recently, evidence has accumulated that some tumor cells express HSPs on the cell surface. The present study confirms this finding and correlates HSP72 cell surface expression, induced by nonlethal heat shock, with an increased sensitivity to interleukin-2-stimulated CD3- natural killer (NK) cells. After nonlethal heat shock, a monoclonal antibody directed against the major heat-inducible 72-kD HSP (HSP72) stains the cell surface of sarcoma cells (ie, Ewing's sarcoma cells or osteosarcoma cells) but not that of normal cells (ie, peripheral blood lymphocytes, fibroblasts, phytohemagglutin-stimulated blasts, B- lymphoblastoid cell lines) or of mammary carcinoma cell line MX-1 carcinoma cells. In this study, we show for the first time a correlation of HSP72 cell surface expression with an increased susceptibility to lysis by NK effector cells. This finding is supported by the following points: (1) HLA-disparate effector cells show similar, elevated lysis of HSP72+ heat-treated sarcoma cells; (2) CD(3-) NK cells, but not CD3+ cytotoxic T lymphocytes, are responsible for the recognition of heat-shocked sarcoma cells; (3) by antibody-blocking studies, an immunogenic HSP72 determinant, which is expressed selectively on the cell surface of heat-treated sarcoma cells could be correlated with NK recognition; (4) the reported phenomenon is independent of a heat-induced, transient downregulation of major histocompatibility complex (MHC) class-I expression; and (5) blocking of MHC class-I-restricted recognition, using either MHC class-I- specific monoclonal antibody W6/32 on the target cells or alpha/beta T- cell receptor monoclonal antibody WT31 on effector cells, also has no inhibitory effect on the lysis of HSP72+ tumor cells. Finally, our in vitro data might have further clinical implications with respect to HSP72 as a stress-inducible, sarcoma-specific NK recognition structure.

Elevated Serum Heat‐Shock Protein 70 Levels in Patients with Acute Infection: Use of an Optimized Enzyme‐Linked Immunosorbent Assay

“…There are indications that Hsp may participate in patho-gen clearance [25] and thus interfere in inflammatory responses [26]. Accumulating evidence has emerged regarding the importance of Hsp 70 in various aspects of cancer regulation [27][28][29][30][31][32][33][34]. It has been speculated on the basis of studies in arthritis that the presence of circulating Hsp 60, another family of Hsp, could be beneficial in juvenile chronic arthritis [35], and the manipulation of the heat-shock response for therapeutic application is a subject of major interest today.…”

Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy

“…A broad screening program of human tumor biopsies revealed that HSP70 is frequently present on the plasma membrane of colon, lung, pancreas, mammary, head and neck and metastases derived thereof [62,151]. Also bone marrow-derived leukemic blasts from patients with hematological malignancies, including acute and chronic myeloid leukemia are frequently HSP70 membrane-positive [152].…”

Anti‐tumour activity of heat‐shock protein 60‐recognizing CD4+ T cells against syngeneic murine renal cell carcinoma

“…Natural killer cells recognize a heat‐inducible immunogenic determinant associated with HSP‐70 on human sarcoma cells in a non‐MHC‐restricted manner [26,27]. In addition, there can be autologous tumour killing induced by heat treatment of fresh tumour cells, through recognition of HSP‐70 by γ/δ T cells [28].…”