Long-term intravital imaging of the multicolor-coded tumor microenvironment during combination immunotherapy
- Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, China
- Tongji Medical College, China
Abstract
The combined-immunotherapy of adoptive cell therapy (ACT) and cyclophosphamide (CTX) is one of the most efficient treatments for melanoma patients. However, synergistic effects of CTX and ACT on the spatio-temporal dynamics of immunocytes in vivo have not been described. Here, we visualized key cell events of immunotherapy-elicited immunoreactions in a multicolor-coded tumor microenvironment, and then established an optimal strategy of metronomic combined-immunotherapy to enhance anti-tumor efficacy. Intravital imaging data indicated that regulatory T cells formed an 'immunosuppressive ring' around a solid tumor. The CTX-ACT combined-treatment elicited synergistic immunoreactions in tumor areas, which included relieving the immune suppression, triggering the transient activation of endogenous tumor-infiltrating immunocytes, increasing the accumulation of adoptive cytotoxic T lymphocytes, and accelerating the infiltration of dendritic cells. These insights into the spatio-temporal dynamics of immunocytes are beneficial for optimizing immunotherapy and provide new approaches for elucidating the mechanisms underlying the involvement of immunocytes in cancer immunotherapy.
Article and author information
Author details
Funding
National Natural Science Foundation of China (91442201)
- Shuhong Qi
- Lisen Lu
- Lei Liu
- Zhihong Zhang
Ministry of Science and Technology of the People's Republic of China (2011CB910401)
- Shuhong Qi
- Hui Li
- Lei Liu
- Qingming Luo
- Zhihong Zhang
National Natural Science Foundation of China (61421064)
- Ling Fu
- Qingming Luo
- Zhihong Zhang
Ministry of Education of the People's Republic of China (2015ZDTD014)
- Shuhong Qi
- Lisen Lu
- Lei Liu
- Zhihong Zhang
Ministry of Science and Technology of the People's Republic of China (Director fund of Wuhan National Laboratory for Optoelectronics)
- Shuhong Qi
- Lisen Lu
- Lei Liu
- Qingming Luo
- Zhihong Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Xuetao Cao, Zhejiang University School of Medicine, China
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of Hubei Provincial Animal Care and Use Committee. The protocol was approved by the Animal Experimentation Ethics Committee of Huazhong University of Science and Technology (reference number: 452). All surgery was performed under ketamine and xylazine, and all intravital imaging experiments were performed under 1-3 % isoflurane in oxygen, every effort was made to minimize suffering.
Version history
- Received: January 28, 2016
- Accepted: October 17, 2016
- Accepted Manuscript published: November 18, 2016 (version 1)
- Version of Record published: December 20, 2016 (version 2)
Copyright
© 2016, Qi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Long-term intravital imaging of the multicolor-coded tumor microenvironment during combination immunotherapy
eLife 5:e14756.
https://doi.org/10.7554/eLife.14756
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
