Article

Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54-61

INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
Nature Medicine (Impact Factor: 27.36). 02/2007; 13(1):54-61. DOI: 10.1038/nm1523
Source: PubMed

ABSTRACT

Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.

Download full-text

Full-text

Available from: Theoharis Panaretakis
  • Source
    • "The finding that systemic administration of Doxil to tumorbearing mice can produce immunomodulatory effects is significant. Previous studies have shown this effect with local administration of doxorubicin only [18] [27] [29]. Our data suggest that there is no inherent difference in the ability of Doxil and doxorubicin to synergize with immunotherapy; however, the data do suggest that, at least in preclinical models, there may be a concentration threshold of doxorubicin within the tumor that is required to induce these effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8 + T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.
    Full-text · Article · Sep 2015 · Neoplasia (New York, N.Y.)
    • "The development of cancer immunotherapeutics has been facilitated in the past decade by an advanced understanding of the roles that various immune cells play in cancer development and cancer treatments (Obeid et al., 2007; Zamarron and Chen, 2011; Klarquist et al., 2014; Nelles et al., 2014). Amongst the various agents assessed for their ability to increase immunogenicity of tumor cells, oncolytic virotherapy has shown promise both in pre-clinical models and in subsequent clinical trials (reviewed in Lichty et al. [2014]). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to both cytotoxic and targeted therapies is a major problem facing cancer treatment. The mechanisms of resistance to unrelated drugs share many common features, including upregulation of detoxifying pathways, activation of pro-survival mechanisms, and ineffective induction of cell death. Oncolytic viruses (OVs) are promising biotherapeutics for cancer treatment that specifically replicate in and lyse cancer cells. In addition to direct viral lysis, the antitumor effects of OVs are mediated via innate and adaptive immune responses, and several adaptation mechanisms such as autophagy appear to contribute to their antitumor properties. Autophagy is a versatile pathway that plays a key role in cancer survival during stressful conditions such as starvation or cytotoxic drug challenges. Autophagy also plays a role in mediating innate and adaptive immune responses by contributing to antigen presentation and cytokine secretion. This role of autophagy in regulation of immune responses can be utilized to design therapeutic combinations using approaches that either stimulate or block autophagy to potentiate therapeutic efficacy of OVs. Additional studies are needed to determine optimal multimodal combination approaches that will facilitate future successful clinical implementation of OV-based therapies.
    No preview · Article · Jun 2015 · Biological Chemistry
  • Source
    • "Recent studies indicate that despite the common view of chemotherapy and immunotherapy as antagonistic, there are synergies between the two approaches. For example, certain chemotherapeutics were described to induce immunogenic cell death37383940. Chemotherapy can also reduce tumor induced immunosuppression by eliminating suppressive populations of immune cells, such as Tregs or myeloid derived suppressor cells [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.
    Full-text · Article · May 2015 · Oncotarget
Show more