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Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models.

Hu H, Qiu Y, Guo M, Huang Y, Fang L, Peng Z, Ji W, Xu Y, Shen S, Yan Y, Huang X, Zheng J, Su C - Oncotarget (2015)

Bottom Line: The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited.However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells.This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area, Fuzhou, China.

ABSTRACT
The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

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CIK cell infiltration in tumor stroma and Ki67 expression in cancer cells(A) Tumor xenografts were collected to prepare the paraffin-embedded sections as aforementioned. Immunohistochemical staining was performed to observe the number and distribution of the infiltrated CD3+ T cells in tumor stroma. For each slice, the number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; original magnification: ×200; ***P<0.001. (B) Immunohistochemical staining was performed to observe the expression of the proliferating cell nuclear antigen Ki67 in tumor cells; original magnification: ×200. (C) The number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup to further compare Ki67 expression in cancer cells; *P<0.05, **P<0.01, ***P<0.001.
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Figure 5: CIK cell infiltration in tumor stroma and Ki67 expression in cancer cells(A) Tumor xenografts were collected to prepare the paraffin-embedded sections as aforementioned. Immunohistochemical staining was performed to observe the number and distribution of the infiltrated CD3+ T cells in tumor stroma. For each slice, the number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; original magnification: ×200; ***P<0.001. (B) Immunohistochemical staining was performed to observe the expression of the proliferating cell nuclear antigen Ki67 in tumor cells; original magnification: ×200. (C) The number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup to further compare Ki67 expression in cancer cells; *P<0.05, **P<0.01, ***P<0.001.

Mentions: Because the anti-tumor effect of Hsp70 is closely related to the regulation of immune functions, the infusion of CIK cells was conducted to partially reconstruct the cellular immune function in the tumor xenograft nude mouse models. After treatment with CIK infusion and adenovirus injections, the tumor xenograft tissues were collected to prepare the sections. The results of immunohistochemical staining showed that a large amount of CD3+ T cells had infiltrated the tumor stroma of xenografts in the AdSurp-Hsp70+CIK treatment group, these cells were distributed in and around the cancer nests, particularly in the strongly positive Survivin tumor xenografts. In the CIK group, less T cells had infiltrated the xenograft tumor stroma, and they had a scattered distribution. The blank control group showed no lymphocytic infiltration (Fig. 5A).


Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models.

Hu H, Qiu Y, Guo M, Huang Y, Fang L, Peng Z, Ji W, Xu Y, Shen S, Yan Y, Huang X, Zheng J, Su C - Oncotarget (2015)

CIK cell infiltration in tumor stroma and Ki67 expression in cancer cells(A) Tumor xenografts were collected to prepare the paraffin-embedded sections as aforementioned. Immunohistochemical staining was performed to observe the number and distribution of the infiltrated CD3+ T cells in tumor stroma. For each slice, the number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; original magnification: ×200; ***P<0.001. (B) Immunohistochemical staining was performed to observe the expression of the proliferating cell nuclear antigen Ki67 in tumor cells; original magnification: ×200. (C) The number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup to further compare Ki67 expression in cancer cells; *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359218&req=5

Figure 5: CIK cell infiltration in tumor stroma and Ki67 expression in cancer cells(A) Tumor xenografts were collected to prepare the paraffin-embedded sections as aforementioned. Immunohistochemical staining was performed to observe the number and distribution of the infiltrated CD3+ T cells in tumor stroma. For each slice, the number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. The results were determined by scoring the stained cell ratio and the staining intensity; original magnification: ×200; ***P<0.001. (B) Immunohistochemical staining was performed to observe the expression of the proliferating cell nuclear antigen Ki67 in tumor cells; original magnification: ×200. (C) The number of positive cells was counted within 5 medium-power magnification fields of view (20× objective lens) under microscope. Each experimental group was divided into a weakly positive Survivin subgroup and a strongly positive Survivin subgroup to further compare Ki67 expression in cancer cells; *P<0.05, **P<0.01, ***P<0.001.
Mentions: Because the anti-tumor effect of Hsp70 is closely related to the regulation of immune functions, the infusion of CIK cells was conducted to partially reconstruct the cellular immune function in the tumor xenograft nude mouse models. After treatment with CIK infusion and adenovirus injections, the tumor xenograft tissues were collected to prepare the sections. The results of immunohistochemical staining showed that a large amount of CD3+ T cells had infiltrated the tumor stroma of xenografts in the AdSurp-Hsp70+CIK treatment group, these cells were distributed in and around the cancer nests, particularly in the strongly positive Survivin tumor xenografts. In the CIK group, less T cells had infiltrated the xenograft tumor stroma, and they had a scattered distribution. The blank control group showed no lymphocytic infiltration (Fig. 5A).

Bottom Line: The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited.However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells.This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area, Fuzhou, China.

ABSTRACT
The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.

Show MeSH
Related in: MedlinePlus