In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway
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Yu-Ling Lin1,2, Nu-Man Tsai3,4, Cheng-Hao Hsieh1
1Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 30068, Taiwan, Republic of China.
Abstract:
Cancer progression is associated with the development of antitumor autoantibodies in patients' sera. Although passive treatment with antitumor antibodies has exhibited remarkable therapeutic efficacy, inhibitory effects on tumor progression by endogenous antitumor autoantibodies (EAAs) have been limited. In this study, we show that P4N, a derivative of the plant lignan nordihydroguaiaretic acid (NDGA), enhanced the production of EAAs and inhibited tumor growth at low noncytotoxic concentrations via its immunoregulatory activity. Intratumoral injection of P4N improved the quantity and quality of EAAs, and passive transfer of P4N-induced EAAs dramatically suppressed lung metastasis formation and prolonged the survival of mice inoculated with metastatic CT26 tumor cells. P4N-induced EAAs specifically recognized two surface antigens, 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase, on the plasma membrane of cancer cells. Additionally, P4N treatment led to B-cell proliferation, differentiation to plasma cells, and high titers of autoantibody production. By serial induction of autocrine and paracrine signals in monocytes, P4N increased B-cell proliferation and antibody production via the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway. This mechanism provides a useful platform for studying and seeking a novel immunomodulator that can be applied in targeting therapy by improving the quantity and quality of the EAAs.
Insights
A plant-derived compound, P4N, boosts endogenous antitumor autoantibodies (EAAs) to inhibit cancer growth and metastasis. This immunomodulatory approach enhances B-cell activity and autoantibody production for potential targeted cancer therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cancer progression often involves antitumor autoantibodies, but their therapeutic impact is limited.
- Endogenous antitumor autoantibodies (EAAs) show potential, yet their inhibitory effects on tumor progression are often insufficient.
Purpose of the Study:
- To investigate the immunomodulatory effects of P4N, a nordihydroguaiaretic acid derivative, on EAA production and its impact on tumor growth.
- To explore P4N's mechanism in enhancing B-cell proliferation and autoantibody production for cancer therapy.
Main Methods:
- Intratumoral injection of P4N in mice with metastatic CT26 tumor cells.
- Passive transfer of P4N-induced EAAs to assess therapeutic efficacy.
- Analysis of B-cell proliferation, differentiation, and antibody titers.
- Investigation of the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway.
Main Results:
- P4N treatment enhanced the quantity and quality of EAAs, significantly suppressing lung metastasis and prolonging survival.
- P4N-induced EAAs recognized cancer cell surface antigens: 78-kDa glucose-regulated protein (GRP78) and F1F0 ATP synthase.
- P4N stimulated B-cell proliferation and differentiation, leading to high autoantibody titers via the LTA4H/activin A/BAFF pathway.
Conclusions:
- P4N acts as an immunomodulator, improving EAA production and function to inhibit tumor growth and metastasis.
- The study elucidates a novel mechanism involving the LTA4H/activin A/BAFF pathway for P4N-induced B-cell activation and autoantibody generation.
- P4N offers a promising platform for developing targeted immunotherapies by enhancing endogenous antitumor responses.
