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Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy.

Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, Monsurró V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM - BMC Genomics (2009)

Bottom Line: These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens.We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).This study provides the first prospective validation of a universal mechanism associated with TSD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, USA. worschecha@mail.nih.gov

ABSTRACT

Background: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.

Results: Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).

Conclusion: This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

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Immunohistochemistry staining of MHC class II positive cells. Scale bars are equal to 1 mm and 10× magnification was applied. (A) 42 days after GLV-1h68 administration HT-29 (left) and GI-101A (right) xenografts were excised, sectioned and labeled for MHCII and vital DNA (Hoechst). In addition, GFP signals from VACV infected cells and transmission images are shown. (B) Overlay of MHCII and GFP signals in HT-29 tumors (left) and GI-101A tumors (right). (C) Uninfected HT-29 (left) and GI-101A (right) xenografts were excised at day 42 and treated identical to their infected counterparts. Tissue sections were stained for MHCII and vital DNA (Hoechst). As expected, no Virus-derived GFP signal could be detected.
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Figure 5: Immunohistochemistry staining of MHC class II positive cells. Scale bars are equal to 1 mm and 10× magnification was applied. (A) 42 days after GLV-1h68 administration HT-29 (left) and GI-101A (right) xenografts were excised, sectioned and labeled for MHCII and vital DNA (Hoechst). In addition, GFP signals from VACV infected cells and transmission images are shown. (B) Overlay of MHCII and GFP signals in HT-29 tumors (left) and GI-101A tumors (right). (C) Uninfected HT-29 (left) and GI-101A (right) xenografts were excised at day 42 and treated identical to their infected counterparts. Tissue sections were stained for MHCII and vital DNA (Hoechst). As expected, no Virus-derived GFP signal could be detected.

Mentions: Macrophage presence/function also played an important role (Figure 4) and was associated with over-expression of major histocompatiblity class II genes supporting the presence of activated macrophages in infected GI-101A xenografts. Furthermore, this prominent and specific infiltration could be substantiated by immunohistochemical analyses that demonstrated a strong peri- and intra-tumoral infiltration of MHC class II-expressing host's cells surrounding virally-infected cancer cells (Figure 5).


Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy.

Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, Monsurró V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM - BMC Genomics (2009)

Immunohistochemistry staining of MHC class II positive cells. Scale bars are equal to 1 mm and 10× magnification was applied. (A) 42 days after GLV-1h68 administration HT-29 (left) and GI-101A (right) xenografts were excised, sectioned and labeled for MHCII and vital DNA (Hoechst). In addition, GFP signals from VACV infected cells and transmission images are shown. (B) Overlay of MHCII and GFP signals in HT-29 tumors (left) and GI-101A tumors (right). (C) Uninfected HT-29 (left) and GI-101A (right) xenografts were excised at day 42 and treated identical to their infected counterparts. Tissue sections were stained for MHCII and vital DNA (Hoechst). As expected, no Virus-derived GFP signal could be detected.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713268&req=5

Figure 5: Immunohistochemistry staining of MHC class II positive cells. Scale bars are equal to 1 mm and 10× magnification was applied. (A) 42 days after GLV-1h68 administration HT-29 (left) and GI-101A (right) xenografts were excised, sectioned and labeled for MHCII and vital DNA (Hoechst). In addition, GFP signals from VACV infected cells and transmission images are shown. (B) Overlay of MHCII and GFP signals in HT-29 tumors (left) and GI-101A tumors (right). (C) Uninfected HT-29 (left) and GI-101A (right) xenografts were excised at day 42 and treated identical to their infected counterparts. Tissue sections were stained for MHCII and vital DNA (Hoechst). As expected, no Virus-derived GFP signal could be detected.
Mentions: Macrophage presence/function also played an important role (Figure 4) and was associated with over-expression of major histocompatiblity class II genes supporting the presence of activated macrophages in infected GI-101A xenografts. Furthermore, this prominent and specific infiltration could be substantiated by immunohistochemical analyses that demonstrated a strong peri- and intra-tumoral infiltration of MHC class II-expressing host's cells surrounding virally-infected cancer cells (Figure 5).

Bottom Line: These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens.We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).This study provides the first prospective validation of a universal mechanism associated with TSD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, USA. worschecha@mail.nih.gov

ABSTRACT

Background: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.

Results: Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).

Conclusion: This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

Show MeSH
Related in: MedlinePlus