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Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.

ABSTRACT: Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced antitumor CD8+ T-cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to slowed tumor growth, enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells, reduced levels of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment, and activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor-infiltrating lymphocytes. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG cotreatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease. Taken together, our findings indicate that 17-DMAG functions as an immune adjuvant in the context of vaccines targeting EphA2.

SUBMITTER: Rao A

PROVIDER: S-EPMC3389149 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.

Rao Aparna A Taylor Jennifer L JL Chi-Sabins Nina N Kawabe Mayumi M Gooding William E WE Storkus Walter J WJ

Cancer research 20120502 13

Ineffective recognition of tumor cells by CD8+ T cells is a limitation of cancer immunotherapy. Therefore, treatment regimens that coordinately promote enhanced antitumor CD8+ T-cell activation, delivery, and target cell recognition should yield greater clinical benefit. Using an MCA205 sarcoma model, we show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the HSP90 client protein EphA2 and the subsequent incr ...[more]

PMID: 22552283

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Project description:177Lu‑DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)‑positive neuroendocrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90‑inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with 177Lu‑DOTATATE. The NET cell lines BON, NCI‑H727 and NCI‑H460, were first characterized with regards to 177Lu‑DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three‑dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. 177Lu‑DOTATATE uptake was observed in the BON and NCI‑H727 cells, while the NCI‑H460 cells exhibited no detectable uptake. Accordingly, 177Lu‑DOTATATE reduced the growth of BON and NCI‑H727 spheroids, while no effect was observed in the NCI‑H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and 177Lu‑DOTATATE exerted synergistic therapeutic effects on the BON and NCI‑H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of γ H2A histone family member X (γH2AX) following combined treatment with onalespib and 177Lu‑DOTATATE. Moreover, flow cytometric analyses revealed a two‑fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate 177Lu‑DOTATATE treatment in a SSTR‑specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and 177Lu‑DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.

Project description:Purpose: Non-Small-Cell Lung Cancer (NSCLC) has gained resistance to common chemo- and radiotherapy due to the oncogenic K-RAS mutations. In this work, lactonic sophorolipids (LSL), a constituent of natural sophorolipids known to inhibit histone deacetylase (HDAC) activity, is used to evaluate its potential anticancer property for the treatment of NSCLC. In addition, ganetespib (GT), a Hsp90 inhibitor, is used for its known antitumor activity in several K-RAS mutant NSCLC cells. We propose, a functional anti-oxidant nanomedicine composed of nanoceria (NC) encapsulated with two-drug cocktail LSL and GT for the assessment of therapeutic efficacy of LSL and targeted combination therapy of NSCLC. NC is an excellent redox platform specifically used to supplement the therapeutic potency of these drugs to target both HDAC inhibition and Hsp90 signaling pathways in NSCLC. Methods: Polyacrylic acid-coated nanoceria (PNC) was formulated and folic acid was conjugated on the surface of PNC using "click" chemistry to target NSCLC and to minimize adverse side effects. Solvent diffusion method was used for the encapsulation of individual drugs and co-encapsulation of drug-cocktail along with an optical dye DiI for diagnosis. We hypothesized that the therapeutic efficacy of LSL will be synergistically accelerated by the inhibition of Hsp90 mechanism of GT and redox activity of NC. Results: For the targeted therapy of NSCLC, A549 cells were used and Chinese hamster ovary (CHO) cells were used as healthy control cells. Results showed more than 40% cells were dead within 24 h when treated with LSL nanodrug. When combined with GT, enhanced ROS signals were detected and more than 80% reduction in cell viability was recorded within 24 h of incubation. Treatments with NC without any drug showed minimal toxicity. Migration assays indicate that the highly metastatic nature of NSCLC is successfully restricted by this combination approach. To validate the effectiveness of this combination therapy various cell-based assays including detection of apoptosis, necrosis and HDAC inhibition of LSL were performed. Conclusion: Functional nanoceria with drug-cocktail LSL and GT is successfully developed for the targeted treatment of undruggable NSCLC. The fluorescence modality helps monitoring the drugs delivery. Results demonstrate the potential therapeutic efficacy of LSL, which is synergistically accelerated by the Hsp90 inhibition mechanism of GT and redox activity of NC.

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Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.

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Combination therapy with HSP90 inhibitor 17-DMAG reconditions the tumor microenvironment to improve recruitment of therapeutic T cells.

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