通过ivospemin和doxorubicin联合治疗耗竭多胺可导致卵巢肿瘤免疫微环境的改变

Polyamines are protonated alkylamines that influence many cellular processes including growth, transcription, and survival. Cancer cells are fully reliant on elevated polyamine pools to sustain their continual proliferation and survival. As such, pharmacological modulation of polyamine metabolism is promising as a cancer metabolic therapeutic strategy. Previous work has linked DFMO-mediated polyamine depletion with pro-inflammatory changes in the tumor microenvironment. Our work aims to evaluate ivospemin, a spermine analogue, in ovarian cancer. Considering nearly three-quarters of late-stage ovarian cancer patients develop resistance to platinum-based chemotherapies and these tumors are usually immunotherapy-insensitive, the aim of our study is to determine the combinatorial efficacy and potential immune-priming properties of ivospemin and doxorubicin. We previously demonstrated that ivospemin treatment decreases viability in a variety of cancer cell lines through depletion of intracellular polyamines via downregulation of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and induction of the polyamine catabolic enzyme spermidine/spermine-N 1 -acetyltransferase (SSAT). Additionally, ivospemin increases the efficacy of gemcitabine and topotecan in vivo by delaying tumor onset and reducing overall tumor burden. Here we examine the potential of combining ivospemin with doxorubicin, a common chemotherapeutic used in platinum-resistant ovarian cancer. Ovarian adenocarcinoma lines treated with ivospemin and doxorubicin exhibit an additive decrease in survival that is associated with changes in polyamine metabolic enzyme activity and depleted overall polyamine levels. Using the syngeneic VDID8+ ovarian model, we evaluated the efficacy of combination treatment in vivo. Co-treated animals exhibited increased median survival, delayed tumor onset, and decreased tumor burden. Polyamine analysis of ascites fluid confirmed decreased polyamine content and N 1 -acetylated spermidine accumulation, consistent with upregulation of SSAT activity. The survival benefit was completely absent in an immunocompromised NSG model indicating significant reliance on the immune system for response. Compared to single agent treatment, ascites from co-treated animals showed an increased presence of CD45+ lymphocytes. While treatment did not influence peritoneal macrophage numbers, the polarization of macrophages was altered with a transition from a predominately M2-like phenotype to an M1-like phenotype following treatment. Additionally, an upregulation of PD-L1 was observed suggesting that treatment may increase sensitivity to immune checkpoint inhibitors (ICIs). Future studies will evaluate ivospemin/doxorubicin in combination with various immunomodulatory drugs such as ICIs, TGFbeta blockade, and CD-40 agonists.