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An epitope-directed mRNA vaccine inhibits tumor metastasis through the blockade of mica/b a1/2 shedding

CELL REPORTS MEDICINE 2025年第3期6卷 101981-101981页

作者： Wang, Rui Wu, Jingni Lin, Yifeng Xiao, Yufei Yang, bin Yao, Sheng Pan, Tianhui Fu, Zhixuan Li, Shuyu Wang, Caihua Zhu, Yongliang Zhejiang Univ Affiliated Hosp 2 Sch Med Lab Gastroenterol Hangzhou Zhejiang Peoples R China Zhejiang Univ Affiliated Hosp 2 Dept Int Healthcare Ctr & Gen Med Sch Med Hangzhou Zhejiang Peoples R China Zhejiang Univ Affiliated Hosp 2 Sch Med Dept Gastroenterol Hangzhou Zhejiang Peoples R China Zhejiang Univ Affiliated Hosp 2 Sch Med Dept Clin Lab Hangzhou Zhejiang Peoples R China Zhejiang Univ Affiliated Hosp 2 Sch Med Dept Hepatobiliary & Pancreat Surg Hangzhou Zhejiang Peoples R China Zhejiang Canc Hosp Dept Colorectal Surg Hangzhou Zhejiang Peoples R China

Antigenic peptide-based mRNA vaccines have been explored for immunotherapeutic use in various types of cancer because of their advantages in activating durable and specific immune responses. However, their role in modulating tumor metastasis is still unclear. Here, we identify a conserved linear epitope-based peptide, Ma3P, located in the proteolytic region of major histocompatibility complex (MHC) class I-related chain A (mica) a3 and further design mCM10-L, an mRNA vaccine that encodes the carrier protein CRM197 and 10 tandem repeats of Ma3P. We demonstrate that vaccination with mCM10-L induces the production of specific antibodies that block mica/b a1/2 shedding, activate CD8+ T cells and natural killer (NK) cells, and significantly inhibit mica/b+ tumor metastasis in mice. Furthermore, mCM10-L stimulation triggers the production of specific antibodies to promote mica/b-mediated immune killing in an in-vitro-interacting human organoid model and humanized mice. Our results indicate the potential clinical application prospects of the mCM10-L vaccine.

关键词： tumor metastasis mica/b epitope mRNA vaccine immune organoid

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mica/b expression is inhibited by unfolded protein response and associated with poor prognosis in human hepatocellular carcinoma

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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 2014年第1期33卷 1-8页

作者： Fang, Liang Gong, Jiuyu Wang, Ying Liu, Rongrong Li, Zengshan Wang, Zhe Zhang, Yun Zhang, Chunmei Song, Chaojun Yang, Angang Ting, Jenny P-Y Jin, boquan Chen, Lihua Fourth Mil Med Univ Dept Immunol Xian 710032 Shaanxi Peoples R China Hosp Hubei Armed Police Corps Wuhan Hubei Peoples R China Fourth Mil Med Univ Dept Pathol Xian 710032 Shaanxi Peoples R China Univ N Carolina Dept Microbiol & Immunol Chapel Hill NC 27599 USA

background: mica/b are major ligands for NK cell activating receptor NKG2D and previous studies showed that the serum level of soluble mica (smica) is an independent prognostic factor for advanced human hepatocellular carcinoma. However, the correlation between cellular mica/b expression pattern and human hepatocellular carcinoma progression has not been well explored. The unfolded protein response is one of the main causes of resistance to chemotherapy and radiotherapy in tumor cells. However, whether the UPR in HCC could regulate the expression levels of mica/b and affect the sensitivity of HCC cells to NK cell cytolysis has not been established yet. Methods: mica/b expression pattern was evaluated by immunohistochemistry and Kaplan-Meier survival analysis was done to explore the relationship between mica/b expression level and patient survival. The protein and mRNA expression levels of mica/b in SMMC7721 and HepG2 cells treated by tunicamycin were evaluated by flow cytometry, Western blot and RT-PCR. The cytotoxicity analysis was performed with the CytoTox 96 Non-Radioactive LDH Cytotoxicity Assay. Results: mica/b was highly expressed in human hepatocellular carcinoma and the expression level was significantly and negatively associated with tumor-node metastasis (TNM) stages. Patients with low level of mica/b expression showed a trend of shorter survival time. The unfolded protein response (UPR) downregulated the expression of mica/b. This decreased protein expression occurred via post-transcriptional regulation and was associated with proteasomal degradation. Moreover, decreased expression level of mica/b led to the attenuated sensitivity of human HCC to NK cell cytotoxicity. Conclusion: These new findings of the connection of mica/b, UPR and NK cells may represent a new concrete theory of NK cell regulation in HCC, and suggest that targeting this novel NK cell-associated immune evasion pathway may be meaningful in treating patients with HCC.

关键词： mica/b Hepatocellular carcinoma Natural killer cell Unfolded protein response Innate immunity

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mica/b expression in macrophage foam cells infiltrating atherosclerotic plaques

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EXPERIMENTAL AND MOLECULAR PATHOLOGY 2014年第1期97卷 171-175页

作者： Ikeshita, Shunji Miyatake, Yukiko Otsuka, Noriyuki Kasahara, Masanori Hokkaido Univ Grad Sch Med Dept Pathol Sapporo Hokkaido 0608638 Japan

Infiltrating macrophages accumulate in fatty streak lesions and transform into foam cells, leading to the formation of atherosclerotic plaques. Inflammatory mechanisms underlying the plaque formation mediated by NKG2D-positive lymphocytes such as CD8(+) T cells, natural killer cells and natural killer T cells have been extensively investigated. Yet, the involvement of the NKG2D system itself remains poorly understood. Recent work in mouse models has shown that blockade of an NKG2D receptor ligand interaction reduces plaque formation and suppresses inflammation in aortae. In this study, we conducted immunohistochemical analysis of NKG2D ligand expression in autopsy-derived aortic specimens. Foam cells expressing NKG2D ligands mica/b were found in advanced atherosclerotic lesions accompanied by a large necrotic core or hemorrhage. Human monocyte-derived macrophages treated in vitro with acetylated low-density lipoproteins enhanced expression of mica/b and scavenger receptor A, thus accounting for NKG2D ligand expression in foam cells infiltrating atherosclerotic plaques. Our results suggest that, as in mice, the NKG2D system might be involved in the development of atherosclerosis in humans. (C) 2014 Elsevier Inc. All rights reserved.

关键词： Atherosclerosis NKG2D mica/b Monocyte-derived macrophage

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Clinical significance of the NKG2D ligands, mica/b and ULbP2 in ovarian cancer: high expression of ULbP2 is an indicator of poor prognosis

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CANCER IMMUNOLOGY IMMUNOTHERAPY 2009年第5期58卷 641-652页

作者： Li, Kui Mandai, Masaki Hamanishi, Junzo Matsumura, Noriomi Suzuki, Ayako Yagi, Haruhiko Yamaguchi, Ken baba, Tsukasa Fujii, Shingo Konishi, Ikuo Kyoto Univ Grad Sch Med Dept Gynecol & Obstet Sakyo Ku Kyoto 6068507 Japan Peking Univ Hosp 1 Dept Gynecol & Obstet Beijing 100034 Peoples R China Natl Hosp Org Kyoto Med Ctr Dept Obstet & Gynecol Fushimi Ku Kyoto 6128555 Japan

To investigate the clinical significance of the expression of the NKG2D ligands mica/b and ULbP2 in ovarian cancer. Eighty-two ovarian cancer patients and six patients without ovarian cancer from Department of Obstetrics and Gynecology of Kyoto University Hospital were enrolled in this study between 1993 and 2003. Expression of mica/b, ULbP2, and CD57 in ovarian cancer tissue and normal ovary tissue was evaluated by immunohistochemical staining, and the relationship of these results to relevant clinical patient data was analyzed. Expression of MICs, ULbP2, and HLA-class I molecules in 33 ovarian cancer cell lines and two normal ovarian epithelial cell lines, as well as levels of soluble MICs and ULbP2 in the culture supernatants, were measured. Expression of mica/b and ULbP2 was detected in 97.6 and 82.9% of ovarian cancer cells, respectively, whereas neither was expressed on normal ovarian epithelium. The expression of mica/b in ovarian cancer was highly correlated with that of ULbP2. Strong expression of ULbP2 in ovarian cancer cells was correlated with less intraepithelial infiltration of T cells and bad prognoses for patients, suggesting that ULbP2 expression is a prognostic indicator in ovarian cancer. The expression of NKG2D ligands did not correlate with the levels of the soluble forms of the ligands. High expression of ULbP2 is an indicator of poor prognosis in ovarian cancer and may relate to T cell dysfunction in the tumor microenvironment.

关键词： Ovarian cancer Tumor immunology NKG2D ligand mica/b ULbP2

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A hypoxia-induced decrease of either mica/b or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

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CELL STRESS & CHAPERONES 2015年第1期20卷 139-147页

作者： Schilling, Daniela Tetzlaff, Fabian Konrad, Sarah Li, Wei Multhoff, Gabriele Tech Univ Munich Klinikum Rechts Isar Dept Radiat Oncol D-80290 Munich Germany German Res Ctr Environm Hlth Helmholtz Ctr Munich Inst Biol & Med Imaging CCG Innate Immun Tumor Biol Munich Germany Univ So Calif Keck Sch Med Dept Dermatol Los Angeles CA 90033 USA

Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and b (mica/b) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1 alpha (HIF-1 alpha) on the membrane expression of these NK cell ligands in H1339 with high and MDA-Mb-231 tumor cells with low basal HIF-1 alpha levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of mica/b and Hsp70 on H1339 and MDA-Mb-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1 alpha revealed that the decreased surface expression of mica/b under hypoxia is dependent on HIF-1 alpha in H1339 cells with high basal HIF-1 alpha levels. Hypoxia and HIF-1 alpha did not affect the mica/b expression in MDA-Mb-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1 alpha in MDA-Mb-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands mica/b and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only mica/b appears to be regulated by HIF-1 alpha.

关键词： Hsp70 mica/b Hypoxia HIF-1 alpha NK cell Immune escape

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Midkine upregulates mica/b expression in human gastric cancer cells and decreases natural killer cell cytotoxicity

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CANCER IMMUNOLOGY IMMUNOTHERAPY 2012年第10期61卷 1745-1753页

作者： Zhao, Shuli Wang, Huijuan Nie, Yunzhong Mi, Qiongyu Chen, Xingguo Hou, Yayi Nanjing Med Univ Nanjing Hosp Affiliated 1 Nanjing 210006 Jiangsu Peoples R China Nanjing Univ Immunol & Reprod Biol Lab Sch Med Nanjing 210093 Jiangsu Peoples R China Nanjing Univ State Key Lab Pharmaceut Biotechnol Nanjing 210093 Jiangsu Peoples R China Nanjing Med Univ Dept Microbiol & Immunol Nanjing 210029 Jiangsu Peoples R China

Midkine (MK) is a heparin-binding growth factor overexpressed in various human cancers. In the current study, a positive correlation was observed between MK expression and mica/b serum levels of gastric cancer patients. In addition, MK transfection significantly increased mica/b expression in gastric cancer cells. The soluble mica/b expression was also elevated. Furthermore, MK transfection inhibited CD107a and Granzyme b expression, thereby suppressing the natural killer (NK) cell cytotoxicity in vitro. The phosphorylation of p38 MAPK and its promotion of CHOP expression were also observed after MK treatment and transfection. CHOP was indirectly bound to the mica/b promoter region by interacting with AP-1, leading to mica/b transcription. Overall, the current study shows that MK expression in tumor cells indirectly suppresses NK cytotoxicity by inducing mica/b expression and suppressing NKG2D expression.

关键词： mica/b Midkine CHOP P38 Tumor immune escape

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NZ28-induced inhibition of HSF1, SP1 and NF-κb triggers the loss of the natural killer cell-activating ligands mica/b on human tumor cells

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CANCER IMMUNOLOGY IMMUNOTHERAPY 2015年第5期64卷 599-608页

作者： Schilling, Daniela Kuehnel, Annett Tetzlaff, Fabian Konrad, Sarah Multhoff, Gabriele Tech Univ Munich Klinikum Rechts Isar Dept Radiat Oncol D-81675 Munich Germany Helmholtz Ctr Munich German Res Ctr Environm Hlth Inst Biol & Med Imaging Munich Germany

The activity of natural killer (NK) cells is regulated by activating and inhibiting receptors, whereby the C-type lectin natural killer group 2D (NKG2D) receptor serves as the major activating receptor on NK cells which recognizes major histocompatibility class I chain-related proteins A and b (mica/b). The mica/b expression has been described to be regulated by the transcription factor heat shock factor 1 (HSF1). Inhibition of heat shock protein 90 (Hsp90) is known to induce the heat shock response via activation of HSF1 which is associated with tumor development, metastasis and therapy resistance and also with an increased susceptibility to NK cell-mediated lysis. Therefore, we compared the effects of Hsp90 inhibitor NVP-AUY922, HSF1 inhibitor NZ28 and HSF1 knockdown on the sensitivity of lung (H1339) and breast (MDA-Mb-231, T47D) cancer cells to NK cell-mediated cytotoxicity and the expression of the NKG2D ligands mica/b. Although NVP-AUY922 activates HSF1, neither the mica/b surface density on tumor cells nor their susceptibility to NK cell-mediated lysis was affected. A single knockdown of HSF1 by shRNA decreased the surface expression of MICb but not that of mica, and thereby, the NK cell-mediated lysis was only partially blocked. In contrast, NZ28 completely blocked the mica/b membrane expression on tumor cells and thereby strongly inhibited the NK cell-mediated cytotoxicity. This effect might be explained by a simultaneous inhibition of the transcription factors HSF1, Sp1 and NF-kappa b by NZ28. These findings suggest that new anticancer therapeutics should be investigated with respect to their effects on the innate immune system.

关键词： Heat shock factor 1 (HSF1) mica/b Natural killer (NK) cells NKG2D NVP-AUY922 NZ28

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Downregulation of mica/b tumor surface expressions and augmented soluble mica serum levels correlate with disease stage in breast cancer

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breast Disease 2022年第1期41卷 471-480页

作者： Kshersagar, Jeevitaa Damle, Mrunal N. bedge, Poonam Jagdale, Rakhi Tardalkar, Kishor Jadhav, Dhanaji Jagadale, Swapnali Toro, Yashwant Sharma, Rakesh Joshi, Meghnad G. Department of Stem Cells & Regenerative Medicine D. Y. Patil Deemed to Be University D. Y. Patil Vidyanagar Maharashtra Kasba Bawda Kolhapur India Stem Plus Biotech Smk Commercial Complex Near Shivaji Maharaj Putla Gaon Bhag Maharashtra Sangli India Department of Pathology Shri Siddhivinayak Ganpati Cancer Hospital Maharashtra Sangli Miraj India Department of Statistics Yashavantrao Chavan Institute of Science Maharashtra Satara India Department of Scientific and Industrial Research Organization Shri Siddhivinayak Ganpati Cancer Hospital Maharashtra Sangli Miraj India Department of Obstetrics and Gynaecology Dr. D y Patil Medical College Hospital and Research Institute Maharashtra Kadamwadi Kolhapur India

ObJECTIVE: In this study, the profiling of the expression of major histocompatibility complex (MHC) class I-related chain A and b (mica/b) in human breast cancer tumor tissue, saliva, and urine samples of breast cancer patients and control is carried out. mica/b is ligand of NKG2D receptor expressed on malignant cells. The release of mica/b from tumor tissue comprises an immune escape mechanism that impairs antitumor immunity. based on this literature we explored the potential of soluble mica (smica) as a marker in breast cancer (bC). METHODS: The expression was profiled by using immunohistochemistry (mica/b), western blot (mica/b) and ELISA (mica). RESULTS: The optical density of western blot of mica/b in different stages of bC illustrated significant difference as per one way analysis of variance and significant difference with stage III and IV by Dunnett's multiple comparisons test respectively. Analysis of smica in serum, saliva and urine of bC patients revealed significantly higher levels (median 41.0 ± 4.1 pg/ml in pre-treatment sera, 181.9 ± 1.6 pg/ml in saliva and 90.7 ± 1.7 pg/ml in urine) than in control (median <1.2 pg/ml). The elevated levels of smica were related to the cancer stage. CONCLUSIONS: The elevated levels of smica were observed in patients with well differentiated cancer while the poor expression of smica was observed in patients with poorly differentiated tumors. Tumor immunity is impaired by the release of mica in the biofluids and may be useful for detection and diagnosis of the stage of bC. © 2022 - IOS Press. All rights reserved.

关键词： breast cancer mica/b smica/b

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Ovarian tumor-associated microRNA-20a decreases natural killer cell cytotoxicity by downregulating mica/b expression

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Cellular & Molecular Immunology 2014年第5期11卷 495-502页

作者： Jingyan Xie Mengna Liu Yujuan Li Yunzhong Nie Qiongyu Mi Shuli Zhao Nanjing First Hospital Nanjing Medical University Nanjing China State Key Laboratory of Reproductive Medicine Nanjing Medical University NanjingChina lmmunology and Reproductive Biology Lab of Medical School Nanjing University Nanjing 210093 jingyan Xie and Mengna Liu contributed equally to this work

MicroRNAs （miRNAs） are a class of small non-coding regulatory RNAs, and changes in miRNAs are involved in tumor origin and progression. Studies have shown that miR-20a is overexpressed in human ovarian cancer tissues and that this miRNA enhances long-term cellular proliferation and invasion capabilities. In this study, a positive correlation between serum miR-20a expression and ovarian cancer stage was observed. We found that miR-20a binds directly to the 3＇-untranslated region of mica/b mRNA, resulting in its degradation and reducing its protein levels on the plasma membrane. Reduction of membrane-bound mica/b proteins, which are ligands of the natural killer group 2 member D （NKG2D） receptor found on natural killer （NK） cells, y＋ T cells and CD8＋ T cells, allows tumor cells to evade immune-mediated killing. Notably, antagonizing miR-20a action enhanced the NKG2D-mediated killing of tumor cells in both in vitro and in vivo models of tumors. Taken together, our data indicate that increased levels of miR-20a in tumor cells may indirectly suppress NK cell cytotoxicity by downregulating mica/b expression. These data provide a potential link between metastasis capability and immune escape of tumor cells from NK cells.

关键词： immune escape mica/b miR-2Oa NKG2D ovarian cancer

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丙戊酸钠上调人肾癌细胞mica/b的表达并增强自然杀伤细胞的抗肿瘤活性

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肿瘤 2012年第9期32卷 689-695页

作者：杨丰强邵阳郭长城施菊妹郑军华同济大学附属第十人民医院泌尿外科上海200072 上海武警医院泌尿外科上海201103 同济大学附属第十人民医院血液科上海200072

目的:观察丙戊酸钠(valproic acid,VPA)对人肾癌细胞主要组织相容性复合体Ⅰ类相关链A/b(major histocompatibility complex classⅠ-related chainA/b,mica/b)表达的影响,比较肾癌细胞经VPA处理前后自然杀伤(natural killer,NK)细胞对其杀伤作用的差异。方法:用0.5～8.0mmol/LVPA分别处理人肾癌786-O和ACHN细胞后,应用FCM检测不同浓度VPA对细胞活力的影响。选择4.0mmol/LVPA处理肾癌细胞,通过实时荧光定量PCR和FCM分别检测肾癌细胞mica/bmRNA和蛋白的表达水平;钙黄绿素释放法和FCM分别检测VPA处理肾癌细胞后NK细胞对其的杀伤作用以及NK细胞的脱颗粒行为。结果:8.0mmol/LVPA处理肾癌细胞48h后,对肾癌细胞活力的影响大于其他处理组(P<0.05);4.0mmol/LVPA处理组肾癌细胞mica/bmRNA和蛋白的表达水平均明显高于未经VPA处理的对照组(P<0.05);4.0mmol/LVPA处理组NK细胞对肾癌细胞的杀伤率明显高于未经VPA处理的对照组(P<0.05),且杀伤率的升高可被抗NKG2D(natural-killer group2,memberD)抗体特异性拮抗;肾癌细胞经4.0mmol/LVPA处理后,其激活NK细胞的脱颗粒作用明显强于未经VPA处理的对照组(P<0.05)。结论:VPA可以明显上调肾癌细胞mica/b的表达,增强NK细胞对其的杀伤活性。

关键词：肾肿瘤丙戊酸杀伤细胞,天然 mica/b 细胞,786-O,ACHN

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