Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma
Abstract Background The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-09815-7 |
| _version_ | 1811323418861109248 |
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| author | Guen Tae Kim Eun Young Kim Su-Hyun Shin Hyowon Lee Se Hee Lee Ki-Young Sohn Jae Wha Kim |
| author_facet | Guen Tae Kim Eun Young Kim Su-Hyun Shin Hyowon Lee Se Hee Lee Ki-Young Sohn Jae Wha Kim |
| author_sort | Guen Tae Kim |
| collection | DOAJ |
| description | Abstract Background The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. Methods The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. Results The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. Conclusions PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent. |
| first_indexed | 2024-04-13T13:54:47Z |
| format | Article |
| id | doaj.art-b867c1e8f1ce434ca17d91a07270e1d7 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T13:54:47Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-b867c1e8f1ce434ca17d91a07270e1d72022-12-22T02:44:14ZengBMCBMC Cancer1471-24072022-07-0122111110.1186/s12885-022-09815-7Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinomaGuen Tae Kim0Eun Young Kim1Su-Hyun Shin2Hyowon Lee3Se Hee Lee4Ki-Young Sohn5Jae Wha Kim6Enzychem LifesciencesEnzychem LifesciencesEnzychem LifesciencesEnzychem LifesciencesEnzychem LifesciencesEnzychem LifesciencesDivision of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Abstract Background The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. Methods The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. Results The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. Conclusions PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.https://doi.org/10.1186/s12885-022-09815-7PLAGUrothelial carcinomaAnti-PD-L1Neutrophil-to-lymphocyte ratio |
| spellingShingle | Guen Tae Kim Eun Young Kim Su-Hyun Shin Hyowon Lee Se Hee Lee Ki-Young Sohn Jae Wha Kim Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma BMC Cancer PLAG Urothelial carcinoma Anti-PD-L1 Neutrophil-to-lymphocyte ratio |
| title | Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma |
| title_full | Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma |
| title_fullStr | Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma |
| title_full_unstemmed | Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma |
| title_short | Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma |
| title_sort | improving anticancer effect of apd l1 through lowering neutrophil infiltration by plag in tumor implanted with mb49 mouse urothelial carcinoma |
| topic | PLAG Urothelial carcinoma Anti-PD-L1 Neutrophil-to-lymphocyte ratio |
| url | https://doi.org/10.1186/s12885-022-09815-7 |
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