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Archived Comments for: Cancer immunotherapy: avoiding the road to perdition

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  1. Inhibitor of immune efficiency

    Zorica Juranic, Institute for Oncology and Radiology of Serbia

    3 November 2004

    The failure of the antitumor effect of cancer vaccines even when they are completely elicited in some of cancer (melanoma) patients is frequently observed .

    This could be due to the enhanced presence of some proteins which could inhibit lytic cytotoxic action of perforin. One of such proteins could be calreticulin.

    Calreticulin exerts plenty of functions which among many others include lectin-like chaperoning, calcium storage and signaling, modulation of gene expression, of cell adhesion, enhancement of phagocytosis of C1q, inhibition of angiogenesis and tumoral growth, and it inhibits C1q-dependent complement activation(1). In higher organisms, calreticulin is present in almost all cell types, except erythrocytes. It is present in a wide spectrum of sub cellular compartments, and it is present together with perforin in cytolytic granule in NK and cytotoxic T cells protecting them from harmful perforin action(2).

    Of especial importance for this story is that it was shown that at a concentration of 2.2 x 10-7 M, calreticulin completely blocked perforin-mediated lysis. The inhibition of lysis was independent of granzyme inactivation or the ability of calreticulin to sequester calcium. Calreticulin regulation of perforin-mediated lysis probably occurs without direct interaction with perforin. It was published that calreticulin stabilizes membranes and doing this, it indirectly prevent polyperforin pore formation (3). It was found that calreticulin is present in parasites (4), in primary, or metastatic human melanoma tissues (5) in bladder human carcinomas (|6)..,.Its presence in the circulation in these patients needs to be determined.

    It is known that anticalreticulin autoantibodies are found in many patient

    with autoimmune diseases. This is an indication for the need of checking the potency of

    these autoantibodies to inhibit blocking activity of calreticulin for perforin induced lyses.

    It seems to me, that calreticulin (used additionally in the trial to enhance the immunogenecity of the vaccine) induced the production of anticalreticulin autoantibodiesas a nus effect, and indirectly enhanced the antitumor action of the vaccine, as it was shown that in an adoptive immunotherapy protocol, dendritic cells pulsed with calreticulin isolated from B16/F10.9 murine melanoma, E.G7-OVA, or EL4 thymoma tumors elicited a CTL response to as yet unknown tumor-derived Ags or the known OVA Ag (7).

    In conclusion, it is a question whether calreticulin present in the circulation, or over expressed on tumor cells inhibits NK, or CTL, or complement cytolytic action to tumor cells, and doing this whether it attenuates the action of elicited potent specific and innate antitumor response.


    1. Ferreira V, Molina MC, Valck C, Rojas A, Aguilar L, Ramirez G, Schwaeble

    W,Ferreira A. Role of calreticulin from parasites in its interaction with

    vertebrate hosts. Mol Immunol. 2004 ;40(17):1279-91.

    2. Andrin C, Pinkoski MJ, Burns K, Atkinson EA, Krahenbuhl O, Hudig D,

    Fraser SA,Winkler U, Tschopp J, Opas M, Bleackley RC, Michalak M.

    Interaction between a Ca2+-binding protein calreticulin and perforin, a

    component of the cytotoxic T-cell granules. Biochemistry.


    3.Fraser SA, Karimi R, Michalak M, Hudig D. Perforin lytic activity is

    controlled by calreticulin.J Immunol. 2000 ;164(8):4150-5.

    4.Ferreira V, Molina MC, Valck C, Rojas A, Aguilar L, Ramirez G, Schwaeble

    W,Ferreira A. Role of calreticulin from parasites in its interaction with

    vertebrate hosts. Mol Immunol. 2004 Mar;40(17):1279-91.

    5.Dissemond J, Busch M, Kothen T, Mors J, Weimann TK, Lindeke A, Goos

    M,Wagner SN. Differential downregulation of endoplasmic reticulum-residing

    chaperones calnexin and calreticulin in human metastatic melanoma. Cancer

    Lett. 2004 Jan 20;203(2):225-31.

    6.Diamandis EP. How are we going to discover new cancer biomarkers? A

    proteomic approach for bladder cancer. Clin Chem. 2004 ;50(5):793-5.7.

    7.Nair S, Wearsch PA, Mitchell DA, Wassenberg JJ, Gilboa E, Nicchitta CV.

    Calreticulin displays in vivo peptide-binding activity and can elicit CTL

    responses against bound peptides. J Immunol. 1999 Jun 1;162(11):6426-32.

    Competing interests

    None declared