Platelet‐activating factor‐receptor in chemotherapy mediated acquired resistance of melanoma (LB495)

Pro‐oxidative stressors suppress host immunity via generating oxidized lipids with Platelet‐activating Factor‐receptor (PAF‐R) agonist activity. Since many chemotherapeutic agents are potent pro‐oxidative stressors, the present studies investigated if chemotherapy could thwart host anti‐tumor immunity against melanoma via PAF‐R activation. We demonstrate that treatment of melanoma cell lines and tumors with chemotherapeutic agents generates PAF‐R‐agonists. In a dual tumor model, we show that intratumoral chemotherapy with melphalan or etoposide of one tumor significantly augments the growth of other (untreated) tumor in wild‐type but not in PAF‐R‐deficient hosts. Chemotherapy‐mediated PAF‐R‐dependent increased tumor growth is blocked by systemic administration of antioxidants and cyclooxygenase‐2 (COX‐2) inhibitors. In addition, depleting antibodies against regulatory T cells (Tregs) significantly attenuated chemotherapy‐mediated enhanced tumor growth, suggesting the role of Tregs. Moreover, using FoxP3 EGFP transgenic mice, we show that COX‐2 inhibitor blocked intratumoral Tregs, indicating that Tregs are downstream to COX‐2. Finally, PAF‐R agonists were identified in perfusates of melanoma patients undergoing isolated limb perfusion with melphalan chemotherapy. These findings provide evidence for a novel pathway by which PAF‐R agonists produced via chemotherapy modulate tumor growth via COX‐2‐Treg pathway. These studies explain some instances of chemotherapy treatment failure and provide potential therapeutic targets that could enhance the overall anti‐tumor effectiveness of chemotherapy. Grant Funding Source : NIH R01 HL062996, AICR 09A062, ACSIRG 4185607, Showalter Research Trust Fund 4485602