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• W2092039954 abstract "Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens—VSV-HIF-2α+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1—from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2αHi, SOX-10Hi, c-mycHi, TYRP1, N-RASloCytclo antigen profile, which differed significantly from the HIF-2αlo, SOX-10lo, c-myclo, TYRP1, N-RASHiCytcHi phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b+ cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses. Previously, we showed that vesicular stomatitis virus (VSV) engineered to express a cDNA library from human melanoma cells (ASMEL, Altered Self Melanoma Epitope Library) was an effective systemic therapy to treat subcutaneous (s.c.) murine B16 melanomas. Here, we show that intravenous treatment with the same ASMEL VSV-cDNA library was an effective treatment for established intra-cranial (i.c.) melanoma brain tumors. The optimal combination of antigens identified from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS+VSV-CYTC-C+VSV-TYRP-1) was ineffective against i.c. B16 brain tumors. In contrast, combination of VSV-expressed antigens—VSV-HIF-2α+VSV-SOX-10+VSV-C-MYC+VSV-TYRP1—from ASMEL which was highly effective against i.c. B16 brain tumors, had no efficacy against the same tumors growing subcutaneously. Correspondingly, i.c. B16 tumors expressed a HIF-2αHi, SOX-10Hi, c-mycHi, TYRP1, N-RASloCytclo antigen profile, which differed significantly from the HIF-2αlo, SOX-10lo, c-myclo, TYRP1, N-RASHiCytcHi phenotype of s.c. B16 tumors, and was imposed upon the tumor cells by CD11b+ cells within the local brain tumor microenvironment. Combining T-cell costimulation with systemic VSV-cDNA treatment, long-term cures of mice with established i.c. tumors were achieved in about 75% of mice. Our data show that the anatomical location of a tumor profoundly affects the profile of antigens that it expresses. During our studies to develop effective oncolytic viruses for cancer therapy, we showed that vesicular stomatitis virus (VSV) not only acts as an oncolytic agent1Barber GN Vesicular stomatitis virus as an oncolytic vector.Viral Immunol. 2004; 17: 516-527Crossref PubMed Scopus (108) Google Scholar,2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar but also serves as a powerful immune adjuvant.2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar,3Galivo F Diaz RM Thanarajasingam U Jevremovic D Wongthida P Thompson J et al.Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus.Hum Gene Ther. 2010; 21: 439-450Crossref PubMed Scopus (69) Google Scholar,4Galivo F Diaz RM Wongthida P Thompson J Kottke T Barber G et al.Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma.Gene Ther. 2010; 17: 158-170Crossref PubMed Scopus (58) Google Scholar,5Wongthida P Diaz RM Galivo F Kottke T Thompson J Melcher A et al.VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling.Mol Ther. 2011; 19: 150-158Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,6Wongthida P Diaz RM Galivo F Kottke T Thompson J Pulido J et al.Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer.Cancer Res. 2010; 70: 4539-4549Crossref PubMed Scopus (87) Google Scholar Thus, therapy of intra-tumorally (i.t.) delivered VSV in the B16-ova model derived predominantly from immune bystander effects of the anti-viral innate immune response at the tumor site.2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar,3Galivo F Diaz RM Thanarajasingam U Jevremovic D Wongthida P Thompson J et al.Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus.Hum Gene Ther. 2010; 21: 439-450Crossref PubMed Scopus (69) Google Scholar,4Galivo F Diaz RM Wongthida P Thompson J Kottke T Barber G et al.Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma.Gene Ther. 2010; 17: 158-170Crossref PubMed Scopus (58) Google Scholar,5Wongthida P Diaz RM Galivo F Kottke T Thompson J Melcher A et al.VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling.Mol Ther. 2011; 19: 150-158Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,6Wongthida P Diaz RM Galivo F Kottke T Thompson J Pulido J et al.Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer.Cancer Res. 2010; 70: 4539-4549Crossref PubMed Scopus (87) Google Scholar In addition, viral oncolysis of B16 metastases in the tumor draining lymph node (TDLN) was significantly more effective at priming adaptive T-cell responses against Tumor Associated Antigens (TAA), and clearing tumor, than was direct i.t. virus.7Qiao J Kottke T Willmon C Galivo F Wongthida P Diaz RM et al.Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy.Nat Med. 2008; 14: 37-44Crossref PubMed Scopus (125) Google Scholar This reflected a potent VSV-mediated activation of APC in the TDLN for presentation of TAA released from metastases undergoing oncolysis.7Qiao J Kottke T Willmon C Galivo F Wongthida P Diaz RM et al.Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy.Nat Med. 2008; 14: 37-44Crossref PubMed Scopus (125) Google Scholar We,2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar,8Wongthida P Diaz RM Pulido C Rommelfanger D Galivo F Kaluza K et al.Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus.Hum Gene Ther. 2011; 22: 1343-1353Crossref PubMed Scopus (63) Google Scholar and others,9Bridle BW Stephenson KB Boudreau JE Koshy S Kazdhan N Pullenayegum E et al.Potentiating cancer immunotherapy using an oncolytic virus.Mol Ther. 2010; 18: 1430-1439Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,10Castelo-Branco P Passer BJ Buhrman JS Antoszczyk S Marinelli M Zaupa C et al.Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer.Gene Ther. 2010; 17: 805-810Crossref PubMed Scopus (26) Google Scholar,11Vigil A Martinez O Chua MA García-Sastre A Recombinant Newcastle disease virus as a vaccine vector for cancer therapy.Mol Ther. 2008; 16: 1883-1890Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar have also enhanced priming of CD8+ T-cell responses against TAA by incorporating specific TAA into the oncolytic virus,2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar,8Wongthida P Diaz RM Pulido C Rommelfanger D Galivo F Kaluza K et al.Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus.Hum Gene Ther. 2011; 22: 1343-1353Crossref PubMed Scopus (63) Google Scholar thereby combining truly systemic delivery of oncolytic viruses with effective tumor vaccination to mobilize therapeutic anti-tumor T-cell responses. However, a major hurdle to cancer immunotherapy is that tumors readily evolve to escape from single antigen specific immune responses.12Drake CG Jaffee E Pardoll DM Mechanisms of immune evasion by tumors.Adv Immunol. 2006; 90: 51-81Crossref PubMed Scopus (526) Google Scholar,13Poschke I Mougiakakos D Kiessling R Camouflage and sabotage: tumor escape from the immune system.Cancer Immunol Immunother. 2011; 60: 1161-1171Crossref PubMed Scopus (134) Google Scholar If immunotherapies are developed to target a broad repertoire of TAAs, it will become increasingly difficult for tumors to lose expression of all of these TAA simultaneously, and/or for highly heterogeneous tumors to maintain sub-dominant clones which already lack expression of a subset of TAA, in order to escape a multi-targeted immune response.14Koos D Josephs SF Alexandrescu DT Chan RC Ramos F Bogin V et al.Tumor vaccines in 2010: need for integration.Cell Immunol. 2010; 263: 138-147Crossref PubMed Scopus (23) Google Scholar In this respect, we previously showed that by inducing “stressful death” of normal cells it was possible to generate autoimmune responses, which were also effective against tumor cells which share antigens with the normal tissue.15Ferrone S Immunotherapy dispenses with tumor antigens.Nat Biotechnol. 2004; 22: 1096-1098Crossref PubMed Scopus (10) Google Scholar,16Jevremovic D Vile R The immune system in cancer: if it isn’t broken, Can we fix it?.in: Stuhler G Walden P Cancer Immune Therapy. Wiley VCH, Germany2002: 204-229Google Scholar,17Kottke T Pulido J Thompson J Sanchez-Perez L Chong H Calderwood SK et al.Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas.Cancer Res. 2009; 69: 7767-7774Crossref PubMed Scopus (25) Google Scholar,18Pardoll DM Inducing autoimmune disease to treat cancer.Proc Natl Acad Sci USA. 1999; 96: 5340-5342Crossref PubMed Scopus (159) Google Scholar,19Parmiani G Tumor immunity as autoimmunity: tumor antigens include normal self proteins which stimulate anergic peripheral T cells.Immunol Today. 1993; 14: 536-538Abstract Full Text PDF PubMed Scopus (75) Google Scholar,20Kottke T Sanchez-Perez L Diaz RM Thompson J Chong H Harrington K et al.Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer.Cancer Res. 2007; 67: 11970-11979Crossref PubMed Scopus (79) Google Scholar Therefore, we combined the concepts of inflammatory killing of normal cells to treat tumors, with the use of VSV as both an oncolytic and adjuvant. We hypothesized that, by expressing a cDNA library of a normal/tumor tissue from systemically delivered, immunogenic VSV, it would be possible to display a very broad repertoire of TAA, which are also expressed on tumors of the same histological type and against which T-cell responses would mediate tumor rejection. Consistent with this, intravenous (i.v.) injection of VSV expressing a cDNA library from normal human prostate induced rejection of established murine prostate tumors, without detectable autoimmunity.21Kottke T Errington F Pulido J Galivo F Thompson J Wongthida P et al.Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.Nat Med. 2011; 17: 854-859Crossref PubMed Scopus (72) Google Scholar In this system, VSV induced inflammatory signals in the TDLN, which activated anti-tumor T-cell responses2Diaz RM Galivo F Kottke T Wongthida P Qiao J Thompson J et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus.Cancer Res. 2007; 67: 2840-2848Crossref PubMed Scopus (227) Google Scholar,7Qiao J Kottke T Willmon C Galivo F Wongthida P Diaz RM et al.Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy.Nat Med. 2008; 14: 37-44Crossref PubMed Scopus (125) Google Scholar,9Bridle BW Stephenson KB Boudreau JE Koshy S Kazdhan N Pullenayegum E et al.Potentiating cancer immunotherapy using an oncolytic virus.Mol Ther. 2010; 18: 1430-1439Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,22Braxton CL Puckett SH Mizel SB Lyles DS Protection against lethal vaccinia virus challenge by using an attenuated matrix protein mutant vesicular stomatitis virus vaccine vector expressing poxvirus antigens.J Virol. 2010; 84: 3552-3561Crossref PubMed Scopus (22) Google Scholar,23Bridle BW Boudreau JE Lichty BD Brunellière J Stephenson K Koshy S et al.Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus.Mol Ther. 2009; 17: 1814-1821Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar,24Cobleigh MA Buonocore L Uprichard SL Rose JK Robek MD A vesicular stomatitis virus-based hepatitis B virus vaccine vector provides protection against challenge in a single dose.J Virol. 2010; 84: 7513-7522Crossref PubMed Scopus (49) Google Scholar,25Geisbert TW Geisbert JB Leung A Daddario-DiCaprio KM Hensley LE Grolla A et al.Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.J Virol. 2009; 83: 7296-7304Crossref PubMed Scopus (214) Google Scholar,26Schwartz JA Buonocore L Suguitan Jr, AL Silaghi A Kobasa D Kobinger G et al.Potent vesicular stomatitis virus-based avian influenza vaccines provide long-term sterilizing immunity against heterologous challenge.J Virol. 2010; 84: 4611-4618Crossref PubMed Scopus (32) Google Scholar against the repertoire of potential TAA encoded by the cDNA library.21Kottke T Errington F Pulido J Galivo F Thompson J Wongthida P et al.Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.Nat Med. 2011; 17: 854-859Crossref PubMed Scopus (72) Google Scholar Similarly, a VSV-cDNA library from human melanoma cells (an Altered Self Melanoma Epitope Library (ASMEL) in the murine context) also treated subcutaneous (s.c.) murine B16 melanomas.27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar In both prostate21Kottke T Errington F Pulido J Galivo F Thompson J Wongthida P et al.Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.Nat Med. 2011; 17: 854-859Crossref PubMed Scopus (72) Google Scholar and melanoma27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar models, re-stimulation of lymph nodes (LN)/splenocytes from mice cured of tumor with the VSV-cDNA library stimulated tumor specific, cytokine recall responses in vitro. Using this assay, we identified 3 VSV-cDNA viruses—VSV-N-RAS/VSV-CYT-C/VSV-TYRP-1—from the ASMEL melanoma VSV-cDNA library which, in combination, but not alone, induced s.c. B16 tumor rejection by priming a Th17 anti-tumor response.27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar The goal of the current study was to investigate whether the ASMEL VSV-cDNA library strategy would show a more generalizable therapy against disseminated disease in other body sites. To test this, we treated mice with intra-cranial (i.c.) B16 tumors as opposed to s.c. with the ASMEL VSV-cDNA library. Here, we show that, in the presence of additional T-cell costimulation with IL-2Cx,28Cho HI Reyes-Vargas E Delgado JC Celis E A potent vaccination strategy that circumvents lymphodepletion for effective antitumor adoptive T-cell therapy.Cancer Res. 2012; 72: 1986-1995Crossref PubMed Scopus (36) Google Scholar intravenously delivered ASMEL cured over 75% of mice bearing 5 days established B16 tumors in the brain. However, to our surprise, the combination of antigens from the ASMEL which treated s.c. B16 tumors (VSV-N-RAS/VSV-CYT-C/VSV-TYRP-1), was ineffective against i.c. B16 brain tumors; in contrast, a different combination of VSV-expressed antigens—VSV-Hypoxia-Inducible Factor 2α (HIF-2α)/VSV-SOX-10/VSV-C-MYC/VSV-TYRP1—identified from the ASMEL, which was highly effective against i.c. B16 brain tumors, had no efficacy against s.c. B16 tumors. Our data show that the site of tumor growth, even of tumors of the same histological type, profoundly affects the profile of potential immunogens expressed by the tumor cells. This may either be through the direct imposition of a niche-specific phenotype upon the tumor cells by the local tumor/immune environment or by selection of a subset of pre-existing clones from the heterogeneous tumor mass, which express different antigen repertoires associated with optimal growth in different niches. Therefore, the design of therapeutic strategies must take into account not only the specific histological type of tumor being treated, but also the antigenic/immunogenic identity imposed by the local tumor microenvironment, which may differ radically between tissue/organ sites. Systemic (i.v.) delivery of VSV-expressing OVA, a model TAA of B16-ova tumors, significantly prolonged survival of mice with established intra-cranial B16-ova tumors (P = 0.0259 compared to VSV-GFP), but was unable to generate any cures (Figure 1a). As we reported previously for s.c. B16-ova tumors which escaped OVA-targeted immunotherapy,29Kaluza KM Thompson JM Kottke TJ Flynn Gilmer HC Knutson DL Vile RG Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants.Int J Cancer. 2012; 131: 844-854Crossref PubMed Scopus (39) Google Scholar i.c. tumors which developed following i.v. VSV-ova had lost expression of the target OVA antigen (data not shown). In contrast to our ability to target OVA, a foreign TAA against which no tolerance exists in C57BL/6 mice, VSV-hgp100, targeting the endogenous self-TAA gp100, against which tolerance is intact in C57BL/6 mice, generated no significant therapy against i.c. B16-ova tumors in vivo (Figure 1b), and all the tumors recovered from these mice still retained unchanged levels of gp100 expression (data not shown). However, although adoptive transfer of naive Pmel hgp100 antigen-specific T cells had no therapeutic effect compared to PBS30Rommelfanger DM Wongthida P Diaz RM Kaluza KM Thompson JM Kottke TJ et al.Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer.Cancer Res. 2012; 72: 4753-4764Crossref PubMed Scopus (50) Google Scholar,31Kaluza KM Kottke T Diaz RM Rommelfanger D Thompson J Vile R Adoptive transfer of cytotoxic T lymphocytes targeting two different antigens limits antigen loss and tumor escape.Hum Gene Ther. 2012; 23: 1054-1064Crossref PubMed Scopus (27) Google Scholar (data not shown) >80% of mice bearing i.c. B16-ova tumors were cured by combining i.v. VSV-hgp100 with adoptive transfer of naive PMEL antigen-specific T cells (Figure 1b)—similar to our results treating s.c. B16 tumors.30Rommelfanger DM Wongthida P Diaz RM Kaluza KM Thompson JM Kottke TJ et al.Systemic combination virotherapy for melanoma with tumor antigen-expressing vesicular stomatitis virus and adoptive T-cell transfer.Cancer Res. 2012; 72: 4753-4764Crossref PubMed Scopus (50) Google Scholar,31Kaluza KM Kottke T Diaz RM Rommelfanger D Thompson J Vile R Adoptive transfer of cytotoxic T lymphocytes targeting two different antigens limits antigen loss and tumor escape.Hum Gene Ther. 2012; 23: 1054-1064Crossref PubMed Scopus (27) Google Scholar These data confirm that B16 melanoma in the brain (a common site of clinical metastases) is amenable to immunotherapy, as we have shown for s.c. disease. We therefore hypothesized that it would be possible to treat i.c. tumors by targeting multiple different self-TAA on the tumor cells using a cDNA library, would raise multiple (weak) T-cell responses against several different self-antigens, which would, cumulatively, be sufficient to impact on tumor growth. Consistent with this, i.v. treatment with the ASMEL VSV-cDNA library, constructed from cDNA of human melanoma cells,27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar significantly extended survival of mice bearing 5 days established i.c. B16-ova tumors (P < 0.0001 compared to VSV-GFP) (Figure 1c). Although the ASMEL VSV-cDNA did not generate any long-term cures, it targeted only self-antigens (OVA is not expressed in the ASMEL) and it was significantly more effective than VSV-mediated expression of either a single self-TAA (gp100, no therapy) (Figure 1b) or a non-tolerized, foreign TAA (VSV-ova) (Figure 1a) in two separate experiments. Previously we had shown that anti-tumor efficacy of VSV-cDNA libraries correlates with the ability of LN/splenocytes from VSV-cDNA library treated, tumor-cured mice to mount an IL-1721Kottke T Errington F Pulido J Galivo F Thompson J Wongthida P et al.Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.Nat Med. 2011; 17: 854-859Crossref PubMed Scopus (72) Google Scholar,27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar or IFN-γ32Boisgerault N Kottke T Pulido J Thompson J Diaz RM Rommelfanger-Konkol D et al.Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse.Mol Ther. 2013; 21: 1507-1516Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar recall response in vitro upon re-stimulation with either tumor targets or the library itself. LN/splenocytes from C57BL/6 mice bearing i.c. B16-ova tumors and treated with the ASMEL, secreted IL-17, and IFN-γ in response to re-stimulation in vitro with the ASMEL (Lane 2) (Figure 2a,b). Interestingly, LN/splenocytes from mice which had no primary tumor, but were treated with ASMEL, secreted significantly reduced amounts of IL-17, relative to tumor-bearing mice, upon in vitro re-stimulation with the ASMEL (Lanes 2 versus 4) (Figure 2a), but did exhibit a similar memory IFN-γ recall response to the ASMEL (Lanes 2 versus 4) (Figure 2b). Consistent with this IFN-γ response being predominantly directed against VSV antigens, although tumor bearing mice treated with either the ASMEL VSV-cDNA library, or with VSV-ova, did not have an IL-17 recall response to VSV-ova (Lane 7) (Figure 2a), VSV-hgp100 (data not shown) or VSV-GFP (data not shown), they did have a Th1, IFN-γ memory response in all cases when they were re-stimulated with VSV (either the ASMEL or VSV-ova)(Lanes 6 and 7) (Figure 2b). This Th1, IFN-γ response was absent unless both in vivo treatment and re-stimulation, included VSV; hence, IFN-γ was not seen on re-stimulation of VSV-ova treated mice with cells (not VSV) not expressing OVA (Lane 10) (Figure 2b) or with re-stimulation with OVA peptide (not expressed by VSV) when in vivo treatment was with VSV-GFP (Lane 11) (Figure 2b). However, treatment with VSV-ova was able to generate a Th1, IFN-γ memory recall response against the foreign encoded OVA antigen, as demonstrated either by re-stimulation with OVA-expressing cells (Lanes 8 and 10) (Figure 2b) or with OVA peptide (Lanes 9 and 10) (Figure 2b). Hence, in the context of i.c. B16, a Th17 memory response indicated priming against ASMEL-encoded TAA, whilst a Th1, IFN-γ response corresponded to priming against the VSV adjuvant or an artificially dominant antigen, such as OVA. We exploited the ability of LN/splenocytes (harvested from all the LN of the mice) from intra-cranial tumor-bearing ASMEL-treated mice to secrete IL-17 upon in vitro re-stimulation with the ASMEL (Lane 2) (Figure 2a) to identify individual VSV-cDNA viruses which encoded proteins that are the immunogenic targets of this IL-17 memory response. Using an assay previously validated to clone immunogenic proteins from VSV-cDNA libraries,21Kottke T Errington F Pulido J Galivo F Thompson J Wongthida P et al.Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.Nat Med. 2011; 17: 854-859Crossref PubMed Scopus (72) Google Scholar,32Boisgerault N Kottke T Pulido J Thompson J Diaz RM Rommelfanger-Konkol D et al.Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse.Mol Ther. 2013; 21: 1507-1516Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar including the ASMEL,27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar we isolated the highest dilution of the ASMEL which was still active in stimulating an IL-17 recall response from LN/splenocytes (Figure 2c). Limiting dilution cloning from this highly diluted stock identified single VSV encoding 5′ cDNA sequences from HIF-2α,33Roda JM Wang Y Sumner LA Phillips GS Marsh CB Eubank TD Stabilization of HIF-2a induces sVEGFR-1 production from tumor-associated macrophages and decreases tumor growth in a murine melanoma model.J Immunol. 2012; 189: 3168-3177Crossref PubMed Scopus (52) Google Scholar SOX-10,34Shakhova O Zingg D Schaefer SM Hari L Civenni G Blunschi J et al.Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma.Nat Cell Biol. 2012; 14: 882-890Crossref PubMed Scopus (181) Google Scholar C-MYC,35Zhuang D Mannava S Grachtchouk V Tang WH Patil S Wawrzyniak JA et al.C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells.Oncogene. 2008; 27: 6623-6634Crossref PubMed Scopus (155) Google Scholar and TYRP-1.27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar,36Shibata K Takeda K Tomita Y Tagami H Shibahara S Downstream region of the human tyrosinase-related protein gene enhances its promoter activity.Biochem Biophys Res Commun. 1992; 184: 568-575Crossref PubMed Scopus (39) Google Scholar Consistent with our previous observations for the treatment of s.c. B16 tumors,27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar re-stimulation of LN/splenocytes from tumor bearing, ASMEL-treated mice with any of these VSV-cDNA individually, in double or triple combinations, did not induce significant IL-17 (Figure 3a). However, when all four were combined, at the same total dose of virus, an IL-17 recall response was induced in vitro at levels approaching that induced by re-stimulation with the intact, un-fractionated ASMEL (Figure 3a). To our surprise, and despite the fact that the ASMEL generated significant therapy against i.c. B16-ova tumors, LN/splenocytes from C57BL/6 mice bearing intra-cranial B16-ova tumors, which had been treated with the ASMEL, did not secrete IL-17 (or IFN-γ) when re-stimulated in vitro with lysates of cultured B16-ova cells (Lane 3) (Figure 2a,b) (Lane 6) (Figure 3a). This was in sharp contrast to our previous findings where LN/splenocytes from mice in which s.c. tumors were cured by treatment with the ASMEL had a Th17 memory response against both the ASMEL and cultured tumor cells in both the B16 and B16-ova models (Figure 3b).27Pulido J Kottke T Thompson J Galivo F Wongthida P Diaz RM et al.Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma.Nat Biotechnol. 2012; 30: 337-343Crossref PubMed Scopus (83) Google Scholar However, the IL-17 recall response was effectively induced from LN/splenocytes of mice with i.c. B16-ova tumors, treated with the ASMEL, upon re-stimulation with tumor cells recovered directly from i.c.-grown B16-ova brain tumors (Lane 8) (Figure 3a). In contrast, LN/splenocytes from mice treated for s.c. B16-ova tumors with the ASMEL could not be re-stimulated with brain tumor-derived B16 targets (Lane 5) (Figure 3b). These data suggested that B16-ova tumors growing in the brain expressed a distinct" @default.
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