Neoplasia最新文献

{"title":"Depletion of regulatory T cells enhances the T cell response induced by the neoantigen vaccine with weak immunogenicity.","authors":"Ruichen Huang, Qiao Zhou, Jiajun Liu, Yang Xia, Yang Jiao, Bi Zhao, Tangtao Feng, Haosu Zhou, Xiuyan Song, Hao Qin, Jun Wang, Lan Cheng, Yunye Ning, Qinying Sun, Yanfang Liu, Xiaoping Su, Yuchao Dong, Wei Zhang","doi":"10.1016/j.neo.2024.101088","DOIUrl":"https://doi.org/10.1016/j.neo.2024.101088","url":null,"abstract":"<p><strong>Background: </strong>The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.</p><p><strong>Methods: </strong>In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.</p><p><strong>Results: </strong>In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.</p><p><strong>Conclusion: </strong>Our research first revealed that inhibiting the normal function of Tregs transformed \"weaker\" neoantigens into \"stronger\" ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.</p>","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"59 ","pages":"101088"},"PeriodicalIF":6.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48Cre/+-LSL-KrasG12D/+ Mice\" [Neoplasia, Volume 14, Issue 9 (2012) 778-787].","authors":"Chinthalapally V Rao, Altaf Mohammed, Naveena B Janakiram, Qian Li, Rebekah L Ritchie, Stan Lightfoot, Awasthi Vibhudutta, Vernon E Steele","doi":"10.1016/j.neo.2024.101081","DOIUrl":"https://doi.org/10.1016/j.neo.2024.101081","url":null,"abstract":"","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"59 ","pages":"101081"},"PeriodicalIF":6.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering and characterization of Hu3A4: A novel humanized antibody with potential as a therapeutic agent against myeloid lineage leukemias.","authors":"Sisi Li, Zhujun Wang, Xiaoping Guo, Yongmin Tang","doi":"10.1016/j.neo.2024.101084","DOIUrl":"https://doi.org/10.1016/j.neo.2024.101084","url":null,"abstract":"<p><p>Leukemia stem cells (LSCs) play a critical role in the initiation, recurrence, and resistance to treatment of leukemia. Eradicating LSCs is crucial for the complete elimination of the disease. CD45RA is identified as an important marker for LSC subsets in acute myeloid leukemia (AML), providing a strategic target for therapy. In this report, we introduce Hu3A4, an innovative humanized CD45RA antibody devised to target LSCs expressing this antigen. Hu3A4 retains the antigen-recognition ability of its parental antibody while removing sequences from the variable region that could elicit human anti-mouse immune reactions. The modified variable regions of the heavy and light chains were intricately fused with the constant regions of human IgG1 heavy and light chains, respectively, producing a humanized antibody that emulates the structure of natural IgG. Hu3A4 was produced through recombinant expression in Chinese Hamster Ovary (CHO) cells, which ensured stable gene integration. In vitro tests revealed that Hu3A4 could effectively target and lyse the cells. Further, in vivo studies highlighted Hu3A4's substantial anti-leukemic activity, significantly prolonging survival times in treated animal models compared to controls (P < 0.01). To summarize, Hu3A4 exhibits remarkable bioactivity and offers a promising therapeutic potential for the treatment of leukemia patients. Progressing Hu3A4 through additional preclinical and clinical studies is crucial to validate its efficacy as a therapeutic agent for leukemia.</p>","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"59 ","pages":"101084"},"PeriodicalIF":6.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-redundant roles of the CCR1 and CCR2 chemokine axes in monocyte recruitment during lung metastasis.","authors":"Alessia G Liner, Merel van Gogh, Marko Roblek, Matthias Heikenwalder, Lubor Borsig","doi":"10.1016/j.neo.2024.101089","DOIUrl":"https://doi.org/10.1016/j.neo.2024.101089","url":null,"abstract":"<p><p>Monocytes and monocyte-derived macrophages facilitate cancer progression and metastasis. Inflammatory monocytes expressing CCR2 are actively recruited to metastatic lungs, where they promote tumor cell extravasation, metastatic outgrowth, and an immunosuppressive environment. The role of CCR1 in this process has remained unclear. We used Ccr1- and Ccr2-deficient mice and two different tumor cells lines, MC38 and LLC1 with and without Ccl2-deficiency in vitro and in vivo. The recruitment of both Ccr1- and Ccr2-deficient monocytes towards the Ccl2 chemokine was significantly impaired, while no substantial recruitment was observed towards Ccl5 in vitro. MC38 and LLC1 Ccl2-deficient tumor cells showed reduced lung metastasis in both Ccr1- and Ccr2-deficient mice when compared to wild-type mice. We detected reduced numbers of macrophages and myeloid cells in both chemokine receptor-deficient mice. Lung metastasis in both Ccr1- and Ccr2-deficient mice could be rescued to the same levels as in wild-type mice by an adoptive transfer of Ccr2-deficient but not Ccr1-deficient monocytic cells. Accumulation of Ccr1-deficient monocytes in the lungs was severely impaired upon intravenous monocyte injection, indicating the importance of this axis in cell recruitment. Moreover, the efficient recruitment of adoptive transferred Ccr2-deficient monocytes to the lungs and the restoration of lung metastasis suggests an involvement of an additional, Ccr2-independent chemokine pathway. This data defines the non-redundant functions of the Ccr1- and Ccr2-chemokine axes in monocyte recruitment and macrophage presence during lung metastasis. While Ccr2 is essential for the release of monocytes from the bone marrow, Ccr1 is primarily responsible for monocyte presence at metastatic sites.</p>","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"59 ","pages":"101089"},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequential treatment of anti-PD-L1 therapy prior to anti-VEGFR2 therapy contributes to more significant clinical benefits in non-small cell lung cancer.","authors":"Qiao-Xin Lin, Wen-Wen Song, Wen-Xia Xie, Yi-Ting Deng, Yan-Na Gong, Yi-Ru Liu, Yi Tian, Wen-Ya Zhao, Ling Tian, Dian-Na Gu","doi":"10.1016/j.neo.2024.101077","DOIUrl":"https://doi.org/10.1016/j.neo.2024.101077","url":null,"abstract":"<p><strong>Objective: </strong>Anti-angiogenic therapy and immune checkpoint blockade therapy are currently important treatments for non-small cell lung cancer. However, the combined use of the two therapies is controversial, and few studies have investigated the effects of different time sequences of the two therapies on treatment outcomes.</p><p><strong>Methods: </strong>The tumor-bearing mouse model was established and the mice were divided into four groups, including AA-ICB sequence group, ICB-AA sequence group, synchronization group and the control group. Immunohistochemistry was used to assess tumor microvessels and PD-L1 expression. Selected immune cell populations were evaluated using flow cytometry. Meta-analysis and clinical information were used to elucidate the clinical effects of administration sequence.</p><p><strong>Results: </strong>We found that anti-PD-L1 treatment followed by anti-VEGFR2 therapy exerts the best inhibitory effect on tumor growth. Different sequences of anti-angiogenic therapy and immune checkpoint blockade therapy resulted in different proportions of tumor microvessels and immune cell populations in the tumor microenvironment. We further revealed that the administration of anti-PD-L1 before anti-VEGFR brought more normalized tumor blood vessels and CD8⁺T cell infiltration and reduced immunosuppressive cells in the tumor microenvironment. Subsequent re-transplantation experiments confirmed the long-term benefits of this treatment strategy. The meta-analysis reinforced that immunotherapy prior to anti-angiogenic therapy or combination therapy have better therapeutic effects in advanced non-small cell lung cancer.</p><p><strong>Conclusion: </strong>Our study demonstrated that the therapeutic effect of anti-angiogenic treatment after immune checkpoint therapy was superior to that of concurrent therapy, whereas anti-angiogenic therapy followed by immunotherapy did not bring more significant clinical benefits than independent monotherapy.</p>","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"59 ","pages":"101077"},"PeriodicalIF":6.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DCZ0014, a novel compound in the therapy of diffuse large B-cell lymphoma via the B cell receptor signaling pathway.","authors":"Shuaikang Chang, Bo Li, Yongsheng Xie, Yingcong Wang, Zhijian Xu, Shuhan Jin, D. Yu, Huaping Wang, Yumeng Lu, Yong Zhang, Ruye Ma, Cheng Huang, Weiming Lai, Xiaosong Wu, Weiliang Zhu, Jumei Shi","doi":"10.21203/rs.3.rs-48447/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-48447/v1","url":null,"abstract":"Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine. In this study, we found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, and induced cell apoptosis. Following treatment with DCZ0014, DLBCL cells accumulated in G0/G1-phase of the cell cycle and showed decreased mitochondrial membrane potential. Additionally, DCZ0014 inhibited DNA synthesis, enhanced DNA damage in DLBCL cells, as well as inhibited Lyn/Syk in B cell receptor signaling pathway. Further experiments demonstrated that DCZ0014 did not significantly affect peripheral blood mononuclear cells. Tumor xenograft model showed that DCZ0014 not only inhibited tumor growth but also extended the survival time of mice. Thus, DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL.","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"212 7","pages":"50-61"},"PeriodicalIF":4.8,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72436607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Hodgkin Lymphoma Cell Lines Are Characterized by a Specific miRNA Expression Profile.\" Neoplasia 2009, Feb;11(2):167-176.","authors":"J. Gibcus, L. Tan, G. Harms, R. Schakel, D. de Jong, T. Blokzijl, P. Möller, S. Poppema, B. Kroesen, A. van den Berg","doi":"10.1016/J.NEO.2017.11.008","DOIUrl":"https://doi.org/10.1016/J.NEO.2017.11.008","url":null,"abstract":"","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"11 1","pages":"226"},"PeriodicalIF":4.8,"publicationDate":"2018-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74400869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses.","authors":"B. Mukherjee, N. Tomimatsu, K. Amancherla, Cristel V. Camacho, N. Pichamoorthy, S. Burma","doi":"10.1158/1538-7445.AM2012-3745","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2012-3745","url":null,"abstract":"Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy owing to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent dual PI3K/mTOR inhibitor that is currently in phase 1/2 clinical trials for advanced solid tumors. Here, we show that NVP-BEZ235 also potently inhibits ATM and DNA-PKcs, the two major kinases responding to ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Consequently, NVP-BEZ235 blocks both nonhomologous end joining and homologous recombination DNA repair pathways resulting in significant attenuation of DSB repair. In addition, phosphorylation of ATMtargets and implementation of the G(2)/M cell cycle checkpoint are also attenuated by this drug. As a result, NVP-BEZ235 confers an extreme degree of radiosensitization and impairs DSB repair in a panel of GBM cell lines irrespective of their Akt activation status. NVP-BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug as a DNA repair inhibitor in vivo. Our results, showing that NVP-BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential utility of NVP-BEZ235 as an effective radiosensitizer for GBMs in the clinic.","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"14 1","pages":"34-43"},"PeriodicalIF":4.8,"publicationDate":"2012-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88970982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition.","authors":"V. A. Venkatesha, L. A. Parsels, J. Parsels, Lili Zhao, S. Zabludoff, D. Simeone, J. Maybaum, T. Lawrence, M. Morgan","doi":"10.1158/1538-7445.AM2011-3919","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2011-3919","url":null,"abstract":"Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 inhibition would sensitize pancreatic cancer stem cells to gemcitabine. We tested this hypothesis by using two patient-derived xenograft models (designated J and F) and the pancreatic cancer stem cell markers CD24, CD44, and ESA. We determined the percentage of marker-positive cells and their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine and the Chk1 inhibitor, AZD7762. We found that marker-positive cells were significantly reduced by the combination of gemcitabine and AZD7762. In addition, secondary tumor initiation was significantly delayed in response to primary tumor treatment with gemcitabine + AZD7762 compared with control, gemcitabine, or AZD7762 alone. Furthermore, for the same number of stem cells implanted from gemcitabine- versus gemcitabine + AZD7762-treated primary tumors, secondary tumor initiation at 10 weeks was 83% versus 43%, respectively. We also found that pS345 Chk1, which is a measure of DNA damage, was induced in marker-positive cells but not in the marker-negative cells. These data demonstrate that Chk1 inhibition in combination with gemcitabine reduces both the percentage and the tumor-initiating capacity of pancreatic cancer stem cells. Furthermore, the finding that the Chk1-mediated DNA damage response was greater in stem cells than in non-stem cells suggests that Chk1 inhibition may selectively sensitize pancreatic cancer stem cells to gemcitabine, thus making Chk1 a potential therapeutic target for improving pancreatic cancer therapy.","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"43 1","pages":"519-25"},"PeriodicalIF":4.8,"publicationDate":"2011-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91335129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy.","authors":"Sun-jin Kim, Jang‐Seong Kim, E. Park, Ju-Seog Lee, Qingtang Lin, R. Langley, Marva Maya, Junqin He, S. Kim, Weihua Zhang, K. Balasubramanian, D. Fan, G. Mills, M. Hung, I. Fidler","doi":"10.1158/1538-7445.AM10-3428","DOIUrl":"https://doi.org/10.1158/1538-7445.AM10-3428","url":null,"abstract":"In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.","PeriodicalId":48716,"journal":{"name":"Neoplasia","volume":"34 1","pages":"286-98"},"PeriodicalIF":4.8,"publicationDate":"2010-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74009150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}