Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.

PURPOSE: Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC. METHODS: In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo. RESULTS: Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses. CONCLUSION: RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.

Secreted cyclophilin A is non-genotoxic but acts as a tumor promoter.

Chronic inflammation is associated with malignant transformation and creates the microenvironment for tumor progression. Cyclophilin A (CypA) is one of the major pro-inflammatory mediators that accumulates and persists in the site of inflammation in high doses over time. According to multiomics analyses of transformed cells, CypA is widely recognized as a pro-oncogenic factor. Vast experimental data define the functions of intracellular CypA in carcinogenesis, but findings on the role of its secreted form in tumor formation and progression are scarce. In the studies here, we exploit short-term in vitro and in vivo tests to directly evaluate the mutagenic, recombinogenic, and blastomogenic effects, as well as the promoter activity of recombinant human CypA (rhCypA), an analogue of secreted CypA. Our findings showed that rhCypA had no genotoxicity and, thus, was neither involved in nor influenced the initiation stage of carcinogenesis. At high doses, rhCypA could disrupt gap junctions in rat liver epithelial IAR-2 cells in vitro by decreasing the expression of connexins 26 and 43 in these cells and inhibit A549 cell adhesion. These data suggested that rhCypA could contribute to epithelial-mesenchymal transition in malignant cells. The research presented here elucidated the role of secreted CypA in carcinogenesis, revealing that it is not a tumor initiator but can act as a tumor promoter at high concentrations.