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Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment

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Cellular & Molecular Immunology 2019年第4期16卷 401-409页

作者： Ganjun Yu Yanfeng Wu Wenying Wang Jia Xu Xiaoping Lv Xuetao Cao Tao Wan National Key Laboratory of Medical Immunology&Institute of Immunology Second Military Medical University800 Xiangyin RoadShanghai 200433China

PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite ***,the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further ***,we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice.A more significant inhibition of tumor growth and a prolongation of survival were observed in the CT26 mouse model after treatment with a combination of PD-1 blockade and decitabine than in mice treated with decitabine or PD-1 blockade *** anti-tumor effect of the PD-1 blockade was enhanced by low-dose *** results of RNA sequencing and whole-genome bisulfite sequencing of decitabine-treated CT26 cells and tumor samples with microsatellite stability from the patient tumor-derived xenograft model have shown that many immune-related genes,including antigen-processing and antigen-presenting genes,were upregulated,whereas the promoter demethylation was downregulated after decitabine ***,decitabine-based tumor microenvironment re-modulation could improve the effect of the PD-1 *** application of decitabine in PD-1 blockade-based immunotherapy may elicit more potent immune responses,which can provide clinical benefits to the colorectal cancer patients with low microsatellite instability or stable microsatellites.

关键词： colorectal cancer decitabine microsatellite stability PD-1 blockade tumor microenvironment

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A novel synergistic therapeutic strategy for colorectal cancer with microsatellite stability

A novel synergistic therapeutic strategy for colorectal canc...

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第十三届全国免疫学学术大会

作者： Ganjun Yu Yanfeng Wu Wenying Wang Jia Xu Xuetao Cao Tao Wan National Key Laboratory of Medical Immunology & Institute of Immunology Navy Military Medical University

Colorectal cancer(CRC) with microsatellite instability-high(MSI-H) has good clinical response in PD-1/PD-L1 blockades immunotherapy. However, the therapeutic efficacy for microsatellite instability-low(MSI-L) and microsatellite stable(MSS) patients needs further improvement. In our previous study, we have demonstrated that low dose Decitabine(5-aza-2’-deoxynucleoside, DAC) as a demethylation drug, could increase the immunogenicity of tumor cells and then recruit more lymphocytes to the tumor tissue, which provided a good tumor microenvironment for the PD-1 *** also found that tumor associated antigens including NY-ESO-1 could be induced or up-regulated by low dose DAC via demethylation of promoter region, which provides targets for immunotherapy. Antigen specific T cell receptor engineered T cells(TCR-T) are potential for solid tumors and attracting more and more attention. Here we prepared the NYESO-1 specific TCR-T cells by lentivirus transfection that recognized the NY-ESO-1157-165 epitope SLLMWITQC of HLA-A2 restricted, and confirmed the specific recognition and anti-tumor effect on T2 cells loaded with cognate peptides and different tumor cell lines with different phenotypes of HLA-A2 and NY-ESO-1 in vitro. Then, we also found that the TCR-T cells could recognize the NY-ESO-1 induced by DAC and showed cytotoxicity on DAC-treated MSS CRC cells in vitro and in immune-deficient mice model. So, we provided with a synergistic therapeutic strategy of the combination DAC and TCR-T cells for CRC with MSS, which may also be effective in other epithelial malignancies.

关键词： colorectal cancer decitabine microsatellite stability T cell receptor tumor immunotherapy

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Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/Oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical *** considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely *** the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint *** aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor *** therapies thus have shown promising results in many clinical trials alone or in *** efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical *** trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair ***,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC *** this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the *** review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in *** underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy microsatellite instability microsatellite stability DNA mismatch repair

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Application of sintilimab combined with anlotinib hydrochloride in the clinical treatment of microsatellite stable colorectal cancer

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World Journal of Gastrointestinal Oncology 2023年第11期15卷 1925-1935页

作者： Rui Feng De-Xin Cheng Xiao-Chen Chen Liu Yang Hao Wu Department of Interventional Medicine Zhejiang Provincial People’s HospitalPeople’s Hospital of Hangzhou Medical CollegeHangzhou 310000Zhejiang ProvinceChina Cancer Center Department of Radiation OncologyZhejiang Provincial People’s HospitalPeople’s Hospital of Hangzhou Medical CollegeHangzhou 310000Zhejiang ProvinceChina Department of Vascular Surgery Zhejiang Provincial People’s HospitalPeople’s Hospital of Hangzhou Medical CollegeHangzhou 310000Zhejiang ProvinceChina

BACKGROUND microsatellite stable(MSS)colorectal cancer(CRC)is a common type of tumor with limited treatment *** and anlotinib hydrochloride are two extensively studied anticancer *** To probe the clinical value of combining sintilimab with anlotinib hydrochloride in MSS CRC *** During the period spanning from April 2019 to April 2022,Zhejiang Provincial People’s Hospital accommodated a cohort of 92 patients diagnosed with MSS CRC who were classified into two distinct groups in our study,the observation group and the control *** control group was administered anlotinib hy-drochloride as their designated therapy,whereas the observation group received the additional treatment of sintilimab in conjunction with the therapy assigned to the control *** administration of treatment occurred in cycles consisting of a duration of 3 wk,and the evaluation of effectiveness took place subsequent to the completion of two consecutive cycles of treatment within both groups.A comparative analysis between the two groups was conducted to assess the short-term efficacy and ascertain the incidence of adverse events transpiring throughout the duration of the treatment *** in the levels of carcinoembryonic Life Questionnaire-Core 30 were compared between the two groups prior to and subsequent to ***,a 1-year follow-up was conducted for both groups of patients,and the survival status was recorded and *** The short-term effectiveness displayed by the observation group surpassed that exhibited by the control group,with a statistically significant discrepancy(76.09%vs 50.00%),reaching a significance level denoted as P<*** the administration of treatment,the observation group manifested a considerable reduction in numerous serum indicators,which were found to be lower than the corresponding pretreatment levels within the same group as well as the post-treatment levels observed in the control group(P<0.0

关键词： microsatellite stability Colorectal cancer Sintilimab Anlotinib hydrochloride Immunity prognosis

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Epidermal growth factor receptor stabilizes programmed death ligand 1 by glycosylation in colorectal cancer with microstatellite instability status

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Journal of Bio-X Research 2019年第1期2卷 1-8页

作者： Xinke Yin Yunlong Wang Shaomei Bai Weixing Feng Lili Feng Wanwen Zhao Mingbiao Wei Xiaolin Pang Shuai Liu Haiyang Chen Fang He Yikan Cheng Junxiang Yin Dalu Zhang Jian Zheng Lei Wang Xinjuan Fan Xiangbo Wan Guangdong Institute of Gastroenterology Institute Sun Yat-sen University Department of Radiation Oncology the Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong Province Department of Pathology the Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong Province China National Center for Biotechnology Development BeijingChina

Programmed death ligand-1(PD-L1)is involved in inhibiting of T lymphocyte proliferation,producing cytokine,cytolytic activity,and suppressing of the immune *** with molecular alterations involved in DNA mismatch repair promote cancer initiation and tumor *** studies show that colorectal cancer(CRC)patients harboring microsatellite instability(MSI)have a higher anti-programmed cell death protein 1/PD-L1 immunotherapy response ratio compared with microsatellite stable subgroup *** underlying mechanism has however remained ***,we found that compared with microsatellite stable samples,PD-L1 was glycosylated and highly expressed both in MSI CRC cell lines and tissue ***,PD-L1 was Nglycosylated at its N35,N192,N200,and N219 sites,and the four glycosylation sites were all responsible for PD-L1 ***,non-glycosylated PD-L1 underwent rapid degradation compared with glycosylated PD-L1 through the 26S proteasome *** faster degradation of the non-glycosylated PD-L1 was ascribed to its binding to glycogen synthase kinase 3b via *** degradation phenotype was,however,not observed for glycosylated ***,glycosylated PD-L1 was up-regulated by activated epidermal growth factor receptor in MSI CRC ***,our results indicate that epidermal growth factor receptor stabilized PD-L1 via glycosylation in MSI CRC cells,uncovering a novel role of PD-L1 in MSI CRC immunosuppression and disease *** study was approved by the Clinical Ethics Review Committee at the Six Affiliated Hospital of Sun Yat-sen University,China(Approval No.2019ZSLYEC-005).

关键词： epidermal growth factor receptor glycogen synthase kinase 3b glycosylation microsatellite instability microsatellite stability programmed death ligand-1

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