Immune escape phenotype of HPV16-associated tumours: MHC class I expression changes during progression and therapy

Mikyšková, Romana; Bubenı́k, Jan; Vonka, V.; Šmahel, Michal; Indrová, M; Bieblová, Jana; Šímová, Jana; Jandlová, T

doi:10.3892/ijo.26.2.521

Cited by 17 publications

(28 citation statements)

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“…Wu (Dr ChienFu Hong), Johns Hopkins University, Baltimore, MD, and TC-1/A9 tumour cell line, deficient in MHC class I molecules were used (18,19). As a second model, spontaneously metastasizing, HPV16-associated MK16/1/IIIABC (MK16) tumour cell line, also MHC class I deficient, was also utilized (19,20 5 cells/ml medium/48 h (7; Vonka and Sobotková, unpublished data). The cell lines were maintained in RPMI-1640 medium supplemented with 10% fetal calf serum, 2 mM L-glutamine and antibiotics (complete medium) and were cultured at 37˚C in a humified atmosphere with 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…HPV16-associated, non-metastasizing, MHC class I positive cell line TC-1, immunogenic in syngeneic B6 mice (17) and two sublines of TC-1, including TC-1/P3C10 displaying a marked down-regulation of MHC class I molecules, kindly provided from the laboratory of Dr T.C. Wu (Dr ChienFu Hong), Johns Hopkins University, Baltimore, MD, and TC-1/A9 tumour cell line, deficient in MHC class I molecules were used (18,19). As a second model, spontaneously metastasizing, HPV16-associated MK16/1/IIIABC (MK16) tumour cell line, also MHC class I deficient, was also utilized (19,20 5 cells/ml medium/48 h (7; Vonka and Sobotková, unpublished data).…”

Section: Methodsmentioning

confidence: 99%

“…51 Cr microcytotoxicity assay. The cytolytic activity of the spleen effector cells was tested using the 51 Cr release assay, as described previously (19,(25)(26)(27). 51 Cr-labelled tumour targets were mixed with the effector cells in various target-toeffector cell ratios in complete RPMI medium supplemented with mercaptoethanol (10 -5 M).…”

Section: In Vitro Depletion Of Cd8mentioning

confidence: 99%

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IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets

Indrová¹,

Bieblová²,

Bubenı́k³

et al. 2008

Int J Oncol

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Abstract.We have established animal models of HPV16-associated tumours with distinct levels of MHC class I expression. This model was used for examination of immune responses, production of cytokines and kinetics of immune cell subsets after IL-12 therapy of minimal residual tumour disease induced by CBA-4A (cyclophosphamide derivative) treatment. Upregulation of cytokine production was detected, compared to control animals without tumours. No differences in Th1/Th2 polarization of the immune responses after immunotherapy in animals bearing tumours with different surface expression of MHC class I molecules were observed. In the spleens of TC-1 (MHC class I + ) but not of TC-1/A9 (MHC class I -) treated tumour-bearing animals, the cytotoxic CD8 + cells detectable in 51 Cr microcytotoxicity assay, were found. In the spleens of TC-1/A9 but not of TC-1 tumourtreated animals, the NK activity measured as the lysis of NK-sensitive YAC-1 targets was detected. Down-regulation of the CD4 + and CD8 + subpopulations in spleens of tumourbearing animals were not restored after therapy. The percentage of CD25 + /CD4 + T regulatory (T reg ) cells in lymph nodes remained unchanged. The cytoreductive chemotherapy led to strong upregulation and accumulation of immunosuppressive immature myeloid Gr-1 + /CD11b + cells (IMC) in the spleens of treated animals. The accumulation of Gr-1 + /CD11b + cells was significantly decreased after subsequent IL-12 immunotherapy. These data suggest that elimination of IMC after IL-12 immunotherapy may be responsible for the improvement of antitumour responses after adjuvant IL-12 vaccination for the treatment of CMRTD.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: In Vitro Depletion Of Cd8mentioning

confidence: 99%

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IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets

Indrová¹,

Bieblová²,

Bubenı́k³

et al. 2008

Int J Oncol

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“…TC-1/A9 tumour cell line, deficient in MHC class I molecules, represents tumour cell derivative which escaped from the selection pressure mediated by the specific immune response (17). Another E6/E7-expressing MHC class I-deficient, spontaneously metastasizing cell line MK16/1/IIIABC (MK16), moderately immunogenic in syngeneic mice, was developed by in vitro co-transfection of murine C57BL/6 kidney cells with a mixture of plasmids carrying activated H-ras oncogene (plasmid pEJ6.6), HPV16 E6/E7 genes (plasmid p16HHMo) and neomycin resistance gene (plasmid pAG60) (18,19). These cell lines were maintained in RPMI-1640 medium supplemented with 10% foetal calf serum, 2 mM L-glutamine and antibiotics (complete medium) and were cultured at 37˚C in a humidified atmosphere with 5% CO 2 .…”

Section: Introductionmentioning

confidence: 99%

NK1.1+ cells are important for the development of protective immunity against MHC I-deficient, HPV16-associated tumours

Indrová

Šímová²,

Bieblová³

et al. 2010

Oncol Rep

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“…27 Further, it has recently been reported by our laboratory that the up-regulation of the MHC class I expression can also occur in vivo during a long-term immunotherapy of the TC-1/A9 (MHC class I negative) tumours, probably due to the production of IFNg by the immune cells in the tumour microenviroment and its vicinity. 32 To investigate the possibility that CpG ODN 1826 in our experimental setting with the TC-1/A9 tumours acts after up-regulation of the MHC class I molecule expression due to the concomitant immunity also through the CD8 1 -dependent mechanism, we performed the in vivo depletion studies. These experiments revealed that the NK 1.1 1 cells but not CD8 1 cells served as effectors in TC-1/A9 tumour inhibition by CpG 1826 ODN.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of unmethylated CpG oligodeoxynucleotides on MHC class I‐deficient and ‐proficient HPV16‐associated tumours

Reiniš

Šímová

Bubenı́k

2005

Intl Journal of Cancer

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Unmethylated oligodeoxynucleotides containing guanine-cytidine dimers (CpG ODN) have been described as potent inducers of selected antitumour immune responses and the immunotherapeutic efficacy of CpG ODN has been examined either alone or as a vaccine adjuvant. We hypothesized that CpG ODN therapy could be an effective tool for immunotherapy of not only conventional MHC class I 1 tumours but also of those tumours that have lost MHC class I expression during their progression. To address this hypothesis, we employed the animal model resembling MHC class I-proficient and -deficient human papilloma virus (HPV) 16-associated tumours. A cell line transformed with HPV16 E6 and E7 oncogenes, TC-1, as a prototype of MHC class I-positive line, and its MHC class I-deficient sublines TC-1/A9 and TC-1/P3C10 were injected into syngeneic C57BL/6 mice and the growing tumours were subjected to immunotherapy with CpG ODN 1826. The therapy started either 1 day after the challenge with the tumour cells or later, when the tumours had reached a palpable size. In both settings, CpG ODN 1826 significantly reduced the growth of MHC class I-proficient and -deficient tumours. Furthermore, we demonstrated that CpG ODN 1585, whose mechanism of action preferably involves indirect activation of the natural killer cells, induced regression of the MHC class I-deficient tumours TC1/A9 but not of the MHC class I-proficient tumours TC-1. This study infers that synthetic CpG ODN have a potential for the therapy of both MHC class I-proficient and -deficient tumours and thus could be also used against tumours that tend to down-regulate their MHC class I expression. ' 2005 Wiley-Liss, Inc.Key words: HPV16; immunotherapy; CpG oligodeoxynucleotides; MHC class I restriction One of the most important and frequent events in the course of the tumour development is a partial or total loss of the MHC class I expression on the tumour cells. [1][2][3] This loss represents an obstacle in the development of efficient immunotherapy of tumours as well as possible explanation for failures of some experimental antitumour immunotherapies based on induction of the Tcell-mediated cytotoxic immune response in clinical trials. Therefore, there is a need for immunotherapeutic protocols that would also be effective for MHC class I-negative tumours. 4,5 Unmethylated oligodeoxynucleotides harboring guanine-cytidine dimers (CpG ODN) that mimic the bacterial DNA are good candidates for such therapeutic agents, since they have been described as potent inducers of the innate and adaptive immune responses, providing the missing ''danger signal'' through the Toll-like receptor 9 (TLR 9) involving pathway. 6 In tumour immunology, CpG ODN have been used in a number of animal studies as adjuvants in experimental vaccinations 7-10 for ex vivo preparation of cellular vaccines as they induce maturation of dendritic cells [11][12][13] and for the therapy of the residual disease after chemotherapy or tumour resection. 14 Moreover, repeated direct intratumoral administration of CpG ODN si...

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Immune escape phenotype of HPV16-associated tumours: MHC class I expression changes during progression and therapy

Cited by 17 publications

References 0 publications

IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets

IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets

NK1.1+ cells are important for the development of protective immunity against MHC I-deficient, HPV16-associated tumours

Inhibitory effects of unmethylated CpG oligodeoxynucleotides on MHC class I‐deficient and ‐proficient HPV16‐associated tumours

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