IL-6 potentiates tumor resistance to photodynamic therapy (PDT)

Abstract

Background and Objective Photodynamic therapy (PDT) is an anticancer modality approved for the treatment of early disease and palliation of late stage disease. PDT of tumors results in the generation of an acute inflammatory response. The extent and duration of the inflammatory response is dependent upon the PDT regimen employed and is characterized by rapid induction of proinflammatory cytokines, such as IL-6, and activation and mobilization of innate immune cells. The importance of innate immune cells in long-term PDT control of tumor growth has been well defined. In contrast the role of IL-6 in long-term tumor control by PDT is unclear. Previous studies have shown that IL-6 can diminish or have no effect on PDT antitumor efficacy. Study Design/Materials and Methods In the current study we used mice deficient for IL-6, Il6−/−, to examine the role of IL-6 in activation of antitumor immunity and PDT efficacy by PDT regimens known to enhance antitumor immunity. Results Our studies have shown that elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor draining lymph node (TDLN) and did not affect primary antitumor T-cell activation by PDT. However, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models. The inhibition of PDT efficacy by IL-6 appears also to be related to regulation of Bax protein expression. Increased apoptosis was observed following treatment of tumors in Il6−/− mice 24 hours following PDT. Conclusions The development of PDT regimens that enhance antitumor immunity has led to proposals for the use of PDT as an adjuvant treatment. However, our results show that the potential for PDT induced expression of IL-6 to enhance tumor survival following PDT must be considered.

Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy

“…PDT can lead to systemic induction of IL-65657, and this cytokine has been studied to possess dual functions, either in enhancing PDT efficacy5859 or inhibiting PDT mediated antitumor immunity60 via regulation of apoptotic proteins. Our PDT results in this study suggest that IL-6 was an antitumor factor, likely by enhancing PDT efficacy via upregulation of Th17 and Tc17 cells.…”

Responses of Cancer Cells Induced by Photodynamic Therapy

“…Although this study did not examine T-cell responses, changes in T-cell function might occur, and we are presently addressing this issue using co-culture methods. In another study, elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor-draining lymph node, and did not affect primary antitumor T-cell activation by PDT; however, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models, in a manner that may be related to regulation of Bax protein expression [77].…”

T-cell mediated anti-tumor immunity after photodynamic therapy: why does it not always work and how can we improve it?

“…Recently there has been substantial progress in the use of checkpoint inhibitors or inhibitors of co-inhibitory pathways such as CTLA4 and PD-1 that can unleash anti-tumor immunity 24 . Although the effects of PDT on the immune system can be either stimulatory or immunosuppressive 8, 11, 25 , when PDT is able to locally destroy tumor cells as well as to create a systemic response then the best hope of cures is achieved 26 .…”

“…IL-6 leads to neutrophil mobilization that may be mediated by activation of several intracellular signaling pathways such as STAT-3, mitogen-activated protein kinases (MAPK), and phosphoinositol 3 kinase (PI3K) 25 . IL-6/STAT-3 signaling is assumed to promote the expression of prosurvival and antiapoptotic proteins 25, 72 .…”

“…IL-6 leads to neutrophil mobilization that may be mediated by activation of several intracellular signaling pathways such as STAT-3, mitogen-activated protein kinases (MAPK), and phosphoinositol 3 kinase (PI3K) 25 . IL-6/STAT-3 signaling is assumed to promote the expression of prosurvival and antiapoptotic proteins 25, 72 . It was shown that IL-6 over-expression in human basal cell carcinoma cell (BCC) lines increased resistance to PDT by decreasing apoptosis via elevation of the anti-apoptotic protein, Mcl-1 25, 73 .…”