Melanoma is one of the deadliest skin cancers in the United States and unlike most other major cancer types; its prevalence is increasing rapidly. Despite having various treatment options including radiation therapy and chemotherapy, curative treatment for metastatic melanoma remains elusive. Immunotherapy has shown promise in inducing clinical responses in a small subset of patients. However, the overall survival rate of patients with metastatic melanoma is disappointing. Thus, it is important to identify factors which limit the efficacy of immunotherapy such as Ipilimumab. Studies have demonstrated that exposure of pro-oxidative stressors including ultraviolet-B irradiation to human and mouse skin generates oxidized lipid mediators with platelet-activating factor (PAF) agonist activity. These UV-B generated PAF agonists act via PAF-receptor (PAF-R) and mediate systemic immunosuppression via cyclooxygenase 2 (COX-2), immunosuppressive cytokine, interleukin 10 (IL-10) and cell type regulatory T cells (Tregs). Importantly, it has been recently shown that UV-B/PAF-R agonists mediated systemic immunosuppression augments the growth of murine B16F10 melanoma tumors in a PAF-R dependent manner. These effects were mediated via up-regulation of IL-10 and Tregs in the tumor microenvironment. Notably, anti-oxidants and depleting antibodies against IL-10 and Tregs (anti-CD25) blocked UV-B/PAF-R agonists-mediated enhanced tumor growth, indicating the involvement of oxidative generated PAF-R agonists and downstream IL-10 and Tregs in immune evasion of B16F10 tumors. Thus, pro-oxidative stressors may play an important role in inhibiting immune-mediated clearance of melanoma and therefore could potentially compromise the efficacy of melanoma immunotherapy, aimed at suppressing immune escape mechanisms. Notably, it is now demonstrated that UV-B-induces a PAF-R dependent up-regulation of the negative co-stimulatory T-cell receptors CTLA-4 and PD-1 in the tumor microenvironment, which have been demonstrated to suppress normal immune responses against tumor antigens. Importantly, it has been shown that PAF-R agonists' induced systemic immunosuppression is mediated via myeloid derived suppressor cells (MDSCs), an immunophenotype known to suppress host anti-tumor immunity against target antigens. The studies in the proposed grant attempt to take initiative in a direction which could have a major impact on treatment options for melanoma. The preclinical studies outlined below will (1) potentially provide novel strategies to increase the efficacy of anti-CTLA-4 and/or anti-PD-1 melanoma immunotherapy, (2) explore mechanisms of how pro-oxidative stressors can inhibit host anti-tumor immunity. In addition, clinical studies will allow direct assessment of whether therapeutic dose of UV-B can generate adequate levels of immunosuppressive PAF-R agonists in patients undergoing phototherapy. These studies will help in determining the impact of PAF-R agonists on the disease outcomes in patients. These studies will also take advantage of various transgenic and knockout mouse models as a tool for our research.

Public Health Relevance

Skin cancer (melanoma) has been one of most deadly cancer in the United States. We propose that ultraviolet-B radiation generated oxidized lipids exhibiting platelet-activating factor (PAF) agonist activity due to their ability to suppress host anti-tumor immunity could compromise the effectiveness of melanoma immunotherapeutic approaches. We will determine whether blockade of PAF could enhance the efficacy of melanoma immunotherapy in mice models and access potential mechanism for this protective effect.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Career Transition Award (K22)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Humble, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wright State University
Schools of Medicine
United States
Zip Code
Thyagarajan, Anita; Sahu, Ravi P (2018) Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization. Integr Cancer Ther 17:210-216
Thyagarajan, Anita; Shaban, Ahmed; Sahu, Ravi Prakash (2018) MicroRNA-Directed Cancer Therapies: Implications in Melanoma Intervention. J Pharmacol Exp Ther 364:1-12
Thyagarajan, Anita; Saylae, Jeremiah; Sahu, Ravi P (2017) Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent-PAF-R-independent signaling pathway. Oncotarget 8:49959-49972
Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan et al. (2016) Radiation therapy generates platelet-activating factor agonists. Oncotarget 7:20788-800
Sahu, Ravi P; Ferracini, Matheus; Travers, Jeffrey B (2015) Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists. Mediators Inflamm 2015:820543
Sahu, Ravi Prakash (2015) Expression of the platelet-activating factor receptor enhances benzyl isothiocyanate-induced apoptosis in murine and human melanoma cells. Mol Med Rep 12:394-400
Ferracini, Matheus; Sahu, Ravi P; Harrison, Kathleen A et al. (2015) Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands. J Invest Dermatol 135:321-323
Hackler, Patrick C; Reuss, Sarah; Konger, Raymond L et al. (2014) Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis. Cancer Growth Metastasis 7:27-32
Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A et al. (2014) Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Res 74:7069-78
Sahu, Ravi P; Konger, Raymond L; Travers, Jeffrey B (2014) Platelet-Activating Factor-Receptor and Tumor Immunity. JSM Cell Dev Biol 2: