Plasmodium immunotherapy combined with gemcitabine has a synergistic inhibitory effect on tumor growth and metastasis in murine Lewis lung cancer models

Xiao Chen; Zhu Tao; Yun Liang; Meng Ma; Dickson Adah; Wenting Ding; Lili Chen; Xiaofen Li; Linglin Dai; Songwe Fanuel; Siting Zhao; Wen Hu; Donghai Wu; Ziyuan Duan; Fang Zhou; Li Qin; Xiaoping Chen; Zhaoqing Yang

doi:10.3389/fonc.2023.1181176

Plasmodium immunotherapy combined with gemcitabine has a synergistic inhibitory effect on tumor growth and metastasis in murine Lewis lung cancer models

Front Oncol. 2023 Oct 17:13:1181176. doi: 10.3389/fonc.2023.1181176. eCollection 2023.

Authors

Xiao Chen^#^{1

2}, Zhu Tao^#^{2

3}, Yun Liang^{2

4}, Meng Ma^{2

5}, Dickson Adah², Wenting Ding³, Lili Chen², Xiaofen Li², Linglin Dai², Songwe Fanuel^{2

6}, Siting Zhao^{2

3}, Wen Hu³, Donghai Wu², Ziyuan Duan², Fang Zhou³, Li Qin³, Xiaoping Chen^{2

3}, Zhaoqing Yang⁷

Affiliations

¹ Department of Medical Oncology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
² State Key Laboratory of Respiratory Disease, Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong, China.
³ CAS-Lamvac (Guangzhou) Biomedical Technology Co., Ltd., Guangzhou, Guangdong, China.
⁴ Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
⁵ The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
⁶ Department of Applied Biosciences and Biotechnology, Faculty of Science and Technology, Midlands State University, Gweru, Zimbabwe.
⁷ Department of Pathogen Biology and Immunology, Kunming Medical University, Kunming, Yunnan, China.

^# Contributed equally.

Abstract

Objective: Our previous studies have demonstrated that Plasmodium immunotherapy (infection) has antitumor effects in mice. However, as a new form of immunotherapy, this therapy has a weakness: its specific killing effect on tumor cells is relatively weak. Therefore, we tested whether Plasmodium immunotherapy combined with gemcitabine (Gem), a representative chemotherapy drug, has synergistic antitumor effects.

Methods: We designed subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) models to test the antitumor effect of Plasmodium chabaudi ASS (Pc) infection in combination with Gem treatment and explored its underlying mechanisms.

Results: We found that both Pc infection alone and Gem treatment alone significantly inhibited tumor growth in the subcutaneous model, and combination therapy was more effective than either monotherapy. Monotherapy only tended to prolong the survival of tumor-bearing mice, while the combination therapy significantly extended the survival of mice, indicating a significant synergistic effect of the combination. In the mechanistic experiments, we found that the combination therapy significantly upregulated E-cadherin and downregulated Snail protein expression levels, thus inhibiting epithelial-mesenchymal transition (EMT) of tumor cells, which may be due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β signaling pathway.

Conclusion: The combination of Pc and Gem plays a synergistic role in inhibiting tumor growth and metastasis, and prolonging mice survival in murine lung cancer models. These effects are partially attributed to the inhibition of EMT of tumor cells, which is potentially due to the blockade of CXCR2/TGF-β-mediated PI3K/Akt/GSK-3β/Snail signaling pathway. The clinical transformation of Plasmodium immunotherapy combined with Gem for lung cancer is worthy of expectation.

Keywords: Plasmodium chabaudi ASS; Plasmodium immunotherapy; anticancer effect; gemcitabine; mouse lung cancer model; synergism.

Grants and funding

This work was supported by grants from the Open Project of the State Key Laboratory Respiratory Disease (grant number: SKLRD-OP-201802), Program Grant of Guangzhou Innovation Leading Team in Sciences and Technologies (grant number: 201909010007) and the Applied Basic Research Projects of Yunnan Province (grant number: 202101AY070001-084).