Immunoregulatory Cyclophilin A Reprograms the Tumor Immune Microenvironment by Changing the Activation and Exhaustion Profile of T Cells and NK Cells in the Model of Melanoma B16 in Vivo.

Abstract

Cold tumors have an immunosuppressive microenvironment (TME) with weak infiltration of functionally active NK and T cells. Such tumors poorly respond to immunotherapies, and different combined approaches are investigated to reprogram cold tumors into hot ones and improve treatment efficacy. The search for novel immunostimulatory factors for the therapy of cold tumors is of particular clinical relevance. Previously, we showed the antitumor effects of recombinant human Cyclophilin A (rhCypA), an analog of proinflammatory secretory CypA, in experimental models in vivo and indicated it as a stimulator of the antitumor immune response and a modulator of the immune TME. In this study, the effect of rhCypA on the functionality of tumor-infiltrating NK and T cells was investigated using the melanoma B16 tumor model in vivo . After rhCypA treatment, T cells in the TME differently expressed the transcription factors Tbet and Eomes and the exhaustion markers PD-1, LAG-3, and TIM3. Tumors of rhCypA-dosed mice contained a higher proportion of activated CD4 + CD25 + T cells and CD8 + T cells with upregulated activation markers CD44 and CD25 and co-stimulatory CD28. Similarly, rhCypA upregulated PD-1, CTLA-4, and CD25 and downregulated exhaustion markers KLRG-1 and LAG-3 in tumor-infiltrating NK cells. After rhCypA treatment, melanoma B16 was actively infiltrated with CD8 + T cells and NK cells with increased perforin and granzyme B production and TNFα-producing CD4 + cells. Thus, rhCypA reprogrammed the immune tumor microenvironment by boosting the accumulation of functionally more active NK and T cells with the enhanced production of cytotoxic factors while modulating their dysfunction and weakening immunosuppression.