Abstract
Calreticulin is recognized as one of the pivotal damage-associated molecular pattern molecules alerting the host of the presence of distressed cells. In this role, calreticulin becomes exposed on the surface of tumor cells treated by several types of cancer therapy including photodynamic therapy (PDT). The goal of the present study was to examine the potential of externally added calreticulin for augmenting antitumor effect mediated by PDT. Recombinant calreticulin was found to bind to mouse SCCVII tumor cells treated by PDT. Compared to the outcome with PDT alone, cure rates of SCCVII tumors grown in immunocompetent C3H/HeN mice were elevated when calreticulin (0.4 mg/mouse) was injected peritumorally immediately after PDT. Such therapeutic gain with PDT plus calreticulin combination was not obtained with SCCVII tumors growing in immunodeficient NOD-scid mice. In PDT-vaccine protocol, where PDT-treated SCCVII cells are used for vaccination of SCCVII tumor-bearing mice, adding recombinant calreticulin to cells before their injection produced improved therapeutic effect. The expression of calreticulin gene was reduced in PDT-treated cells, while no changes were observed with the expression of this gene in tumor, liver, and spleen tissues in PDT-vaccine-treated mice. These findings reveal that externally added recombinant calreticulin can boost antitumor response elicited by PDT or PDT-generated vaccines, and can thus serve as an effective adjuvant for cancer treatment with PDT and probably other cancer cell stress-inducing modalities.
Highlights
Calreticulin is primarily ER-residing chaperone protein with a broad array of cellular functions, including maintenance of adequate calcium levels, protein folding and trafficking, gene transcription regulation, cell adherence and migration, apoptosis and dead cell clearance, and immune responses [1, 2]
Such surface-exposed calreticulin serves as a powerful mobilizing signal to the immune system, which has inspired recognition of calreticulin as one of the most important damage-associated molecular patterns (DAMPs) [5]
The Photodynamic therapy (PDT)-generated vaccine protocol with SCCVII tumor model developed in our laboratory, centers on preparing single-cell cancer vaccines by using in vitro PDT-treated SCCVII cells postincubated in culture for 16 h and injected peritumorally into mice bearing SCCVII tumors [19]
Summary
Calreticulin is primarily ER-residing chaperone protein with a broad array of cellular functions, including maintenance of adequate calcium levels, protein folding and trafficking, gene transcription regulation, cell adherence and migration, apoptosis and dead cell clearance, and immune responses [1, 2]. Cancer therapymediated lethal insults that involve stress induction in the ER induce the translocation of calreticulin to the outer leaflet of the plasma membrane by an active process occurring before the appearance of morphological signs of apoptosis [3, 4] Such surface-exposed calreticulin serves as a powerful mobilizing signal to the immune system, which has inspired recognition of calreticulin as one of the most important damage-associated molecular patterns (DAMPs) [5]. Photodynamic therapy (PDT) belongs to cancer modalities capable of inducing an abundance of DAMPs including surfaceexposed calreticulin [5, 8] This therapy is established clinically for treatment of various malignant and non-oncological lesions [9]. With PDT mediated by photosensitizer chlorin e6 (ce6), we detected cell surfaceexposed calreticulin as early as 15 min post-treatment (Korbelik, unpublished)
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