Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer

Yazawa, Takuya; Kamma, Hiroshi; Fujiwara, Masachika; Matsui, Miwa; Horiguchi, Hisashi; Satoh, Hiroaki; Fujimoto, Manato; Yokoyama, Kôichi; Ogata, Takesaburo

doi:10.1002/(sici)1096-9896(199901)187:2<191::aid-path206>3.0.co;2-3

Cited by 80 publications

(59 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[26][27][28][29][30][31] H1688, H441, and A549 were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA), and LC2/ad was obtained from the Riken Bioresource Center (Ibaraki, Japan). Non-small-cell lung cancer (NSCLC) cells were cultivated in Dulbecco's modified Eagle's medium, and SCLC cells were cultured in RPMI-1640 medium.…”

Section: Materials and Methods Cultured Lung Cancer Cellsmentioning

confidence: 99%

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Sakaeda

Sato

Ishii

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cellspecific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.

show abstract

Section: Materials and Methods Cultured Lung Cancer Cellsmentioning

confidence: 99%

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Sakaeda

Sato

Ishii

et al. 2013

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, some tumors do not express major histocompatibility complex (MHC) molecules so that these tumor cells do not elicit sufficient anti-tumor immunity [15,16]. In other cases, tumor cells fail to generate new antigen or tumor-specific antigens; and as a result they are unable to evoke immune recognition and tumor destruction because of low intrinsic immunogenicity and tumor-associated immunosuppression [17,18].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Cao

Wang

et al. 2007

Cell Res

View full text Add to dashboard Cite

Regulatory T cells (Treg) play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Th1 responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4+CD25+ T cells from the immunized mice. Moreover, CD4+CD25+Foxp3+ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naïve mice. Further analysis showed that the serum of immunized mice contains a high level of anti-CD25 antibody (about 30 ng/ml, p<0.01 vs controls). Consistent with a role of anti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naïve mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4+CD25+Foxp3+ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Th1 response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.

show abstract

“…The human SCLC cell lines (TKB15, TKB16, and TKB17), 4 and the human NB cell lines (LA-N-1, LA-N-2, and LA-N-5) (purchased from Riken Cell Bank, Tsukuba, Japan), NH12 (provided by Cell Resource Center for Biomedical Research, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan), and SK-N-DZ (kindly provided by Dr. M. Kaneko, Department of Pediatric Surgery, University of Tsukuba, Tsukuba, Japan), were grown in RPMI 1640 medium. The human nonneuroendocrine cancer cell lines, TKB5 (large cell lung cancer) 4 and HeLa (purchased from Riken Cell Bank), were grown in Dulbecco's modified Eagle's medium.…”

Section: Cells and Cell Culturementioning

confidence: 99%

“…1,2 Both are less associated with tumor-infiltrating lymphocytes, which are morphological findings of anti-tumor immunity, and show a more severe reduction in major histocompatibility complex (MHC) than nonneuroendocrine cancers. [3][4][5] The MHC expressed on the cell surface is indispensable for contact with T lymphocytes. Class I MHC (MHC-I) expressed on cancer cells plays an important role in the killer T lymphocytemediated immune response.…”

mentioning

confidence: 99%

“…23 We recently clarified that SCLC, among various histological types of lung cancer, showed a severe reduction of MHC caused by a deficiency of CIITA expression. 4 Because a reduction of MHC has also been reported in NB 7 and because the E-box, the consensus binding motif of HASH-1, L-myc, and N-myc, 22 is located in CIITA promoter IV, it has been proposed that NB also has a deficiency of CIITA and the bHLH transcription factors overexpressed in SCLC and NB modulate the IFN-␥-inducible CIITA expression. This study demonstrates that the overexpressed HASH-1, L-myc, and N-myc in SCLC and NB competitively bind to the E-box in CIITA promoter IV and repress the transcriptional activity, that IFN-␥ upregulates HASH-1 expression, and that L-myc and N-myc are involved in HASH-1 expression.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Complicated Mechanisms of Class II Transactivator Transcription Deficiency in Small Cell Lung Cancer and Neuroblastoma

Yazawa

Ito

Kamma

et al. 2002

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) and neuroblastoma (NB), the most aggressive adult and infant neuroendocrine cancers, respectively, are immunologically characterized by a severe reduction in major histocompatibility complex (MHC) that is indispensable for anti-tumor immunity. We had reported that the severe reduction of MHC in SCLC was caused by a deficient interferon ( Small cell lung cancer (SCLC) and neuroblastoma (NB) are the most aggressive adult and infant neuroendocrine neoplasms, respectively.

show abstract

Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer

Cited by 80 publications

References 33 publications

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

Complicated Mechanisms of Class II Transactivator Transcription Deficiency in Small Cell Lung Cancer and Neuroblastoma

Contact Info

Product

Resources

About