Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide

Abstract

The antitumor effectiveness of cyclophosphamide (CTX) and other chemotherapeutics was shown to rely not only on direct cytotoxicity but also on immunogenic tumor cell death and systemic immunomodulatory mechanisms, including regulatory T cell (Treg) depletion, Th1 cell polarization, type I interferon (IFN) and proinflammatory cytokine production. IFN regulatory factor (IRF)-1 is a transcriptional regulator of IFNs and IFN-inducible genes, involved in the control of Th1 and Treg differentiation and in sterile inflammation. Aim of this study was to explore the role of IRF-1 in CTX-induced antitumor effects and related immune activities. This study shows for the first time that IRF-1 is important for the antitumor efficacy of CTX in mice. Moreover, experiments in tumor-bearing C57BL/6 mice showed that Irf1 gene expression in the spleen was transiently increased following CTX administration and correlated with the induction of Th1 cell expansion and of Il12p40 gene expression, which is the main Th1-driving cytokine. At the same time, CTX administration reduced both Foxp3 expression and Treg cell percentages. These effects were abrogated in Irf1 mice. Further experiments showed that the gene and/or protein expression of caspase-1, iNOS, IL-1β, IL-6 and CXCL10 and the levels of nitric oxide were modulated following CTX in an IRF-1-direct- or -indirect-dependent manner, and highlighted the importance of caspase-1 in driving the sterile inflammatory response to CTX. Our data identify IRF-1 as important for the antitumor efficacy of CTX and for the regulation of many immunomodulatory activities of CTX, such as Th1 polarization, Treg depletion and inflammation.

Blocking inflammation to improve immunotherapy of advanced cancer

“…61 Of note, low-dose cyclophosphamide can also induce Treg depletion by inhibiting their proliferation and intratumoral migration and to dampen their activity by decreasing the FOXP3 and GITR expression. [62][63][64][65][66] Consistent with the above findings, a very recent review 67 discussed cyclooxygenase-2 inhibitors among drugs under investigation in combination with anti-PD-1 antibody immunotherapy.…”

“…More recently, we demonstrated the effectiveness of combination therapy with the anti‐PD‐1 antibody, nivolumab, and cyclophosphamide, an immunomodulatory chemotherapy agent that down‐regulates macrophage activity and inhibits pro‐inflammatory cytokine synthesis, thereby synergistically enhancing the action of immunotherapy . Of note, low‐dose cyclophosphamide can also induce Treg depletion by inhibiting their proliferation and intratumoral migration and to dampen their activity by decreasing the FOXP3 and GITR expression …”

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

“…IRF-1 accumulation in CD4 + T cells is involved in Th1 development and in the maturation of CD8 + T-cells. It is also involved in the differentiation and maturation of dendritic cells and in the inhibition of the development of regulatory T (Treg) cells [99][100][101]. On the other hand, patients with immune-mediated diseases such as inflammatory bowel disease showed dysregulated T cell proliferation, which can lead to anxiety-like behavior [102].…”

Adjuvant Effect of Molecular Iodine in Conventional Chemotherapy for Breast Cancer. Randomized Pilot Study

“…In the context of cancer, IRF1 is required for Th1 polarization in NK cells, mature CD8 + T cells, and M1 macrophages. In addition, IRF1 is involved in the negative regulation of Treg cells leading to the reactivation of an anti-tumor immune response [35]. Our analysis also shows that although IRF1 can stimulate genes related to both Th1 (STAT4, T-bet/TBX21, IL12RB1, and IL12RB2) and Th2 (IRF4, E2F1, and FOXP3) responses, the predominant activation type in both I2-treated groups seemed to be Th1.…”