Recombinant Human Cyclophilin A in Combination with Adoptive T-cell Therapy Improves the Efficacy of Cancer Immunotherapy in Experimental Models in vivo

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Anastasiia A. Kalinina^1,a*, Dmitry B. Kazansky¹, and Ludmila M. Khromykh¹

¹N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 115478 Moscow, Russia

^* To whom correspondence should be addressed.

Received December 15, 2022; Revised February 8, 2023; Accepted February 8, 2023

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Adoptive T-cell therapy (ACT) is successfully applied in cancer treatment; however, its efficiency can be limited by a low viability, short persistence time, and loss of functional activity of T-cells after adoptive transfer. The search for novel immunomodulators that can improve the viability, expansion, and functions of T-cells after their infusion with the minimal side effects could contribute to the development of more efficient and safe ACT strategies. Recombinant human cyclophilin A (rhCypA) is of particular interest in this respect, as it exhibits pleiotropic immunomodulatory activity and stimulates both innate and adaptive anti-tumor immunity. Here, we evaluated the effect of rhCypA on the efficacy of ACT in the mouse EL4 lymphoma model. Lymphocytes from transgenic 1D1a mice with an inborn pool of EL4-specific T-cells were used as a source of tumor-specific T-cells for ACT. In models of immunocompetent and immunodeficient transgenic mice, the course (3 days) rhCypA administration was shown to significantly stimulate EL4 rejection and prolong the overall survival of tumor-bearing mice after adoptive transfer of lowered doses of transgenic 1D1a cells. Our studies showed that rhCypA significantly improved the efficacy of ACT by enhancing the effector functions of tumor-specific cytotoxic T-cells. These findings open up the prospects for the development of innovative strategies of adoptive T-cell immunotherapy for cancer using rhCypA as an alternative to existing cytokine therapies.

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KEY WORDS: cyclophilin A, adoptive cell therapy, cytokine therapy, anti-cancer therapy, T-cell receptor, cytotoxic T lymphocyte, immunodeficiency, transgenesis

DOI: 10.1134/S0006297923050024

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