Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects
Authors: Guoyou Yang
Xiaomei Zhang
Fen Xu
Jianzhou Wang
Tao Du
Lin Cheng
Yiming Li
Shuang Zhang
Xiaolei Chen
Yuquan Wei
Hongxin Deng
Junfeng Zhang
Lei Dai
Dechao Yu
Hongwei Tian
Yang Yang
Gang Shi
Journal: BMC Cancer (2014)
Discipline: CLINICAL MEDICINE
Keywords: tumor cell vaccine; immunogenic; IL-18; GM-CSF; antitumor efficacy
Affiliations: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, The People's Republic of China. .

Abstract:  Background: Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. Methods: The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. Results: The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes. Conclusions: These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity. 

Retracted: No

PubPeer comments:
 Some figures in fig5B was copied from another paper from the same group  Antitumor effects obtained by autologous Lewis lung cancer cell vaccine engineered to secrete mouse Interleukin 27 by means of cationic liposome ![file] , 
 Dear Dr. Lycoperdon Lividum Thank you very much for pointing out these errors of Fig 5B in our published work. We have checked our original data and found wrong figures by mistake some days ago. We will contact the editorial department of BMC Cancer as soon as possible to submit the right picture and ask for a corrigendum. Thank you again for helping us find and correct the mistake. Sincerely yours Hongxin Deng , 
 #2 Dear Dr. Deng: Thank you for your reply. It would be appreciated if you were to also post the u201dright pictureu201d here also. , 
 Fig 6A, mGM-CSF and mIL-18 have duplicates. ![file] , 
 #4 Dear Dr. Paraburkholderia Caffeinilytica , Thank you very much for pointing out the mistake of Figure 6A in our published work. We have carefully investigated our raw data and found that this error was inadvertently made during the preparation of the manuscript. We will contact the journal editorial office as soon as possible to correct the error. Hongwei , 
 Correction published does not seem to address the comment in #4. A Correction to this article was published on 17 January 2020 Following publication of the original article [1], the authors reported an error in Fig. 5 of this article, graphs presenting FCM and immunofluorescent for CD4T, CD8T and NK cell of the Control Groups (LL2, LL2-irradation, MCS-irradiation) were inadvertently duplicated from another parallel experiment. The correct version of this figure appears below. To the best of our knowledge, this does not affect the conclusions. We apologize for the error. ![file] , 
 Unfortunately, after comparing the two corrected figures, it appears that these two figures may still have overlapping images. The recordkeeping techniques seemingly on display here do not leave this reader with confidence that the results have not been affected. I will alert both journals again. *** ![file] ,