Purpose: Our immune system can recognize non-self antigens presented by the tumor cells and then activated to eradicate them. It is generally known that antigen specific cytotoxic T lymphocytes (CTLs) play pivotal roles in this mechanism. Despite the presence of such well-established defense mechanism, many cancer cells have evolved to escape from immune system by expressing self-antigens, which cannot induce CTL-mediated immunological rejection. This study aims to induce anticancer response, foreignizing the tumor cells to be recognized by CTLs with a tumor microenvironment-sensitive polymeric conjugate.
Methods: In this study, we have prepared polymeric conjugate consisting matrix metalloproteinase (MMP)-responsive peptide as a cleavable linker, hyaluronic acid (HA) as a targeting moiety, and ovalbumin (OVA) as a model foreign antigen. To deliver OVA efficiently into the tumor cells, the MMP9-responsive 8-amino acids peptide linker (PLGLWADR) was introduced to HA grafted with poly (ethylene glycol) (PEG), thereby inducing the separation of PEG shell from HA backbone at MMP9 abundant circumstance. We demonstrated the hypothesis with foreign antigen presentation efficiency, tumor tissue accumulation capacity, and CTL-mediated immunological response inducing capability of polymeric conjugate.
Results: From a cellular uptake study using confocal microscopy and flow cytometry, the polymeric conjugate showed MMP9-dependant receptor-mediated endocytosis. We also demonstrated that the conjugate could enhance OVA presentation on cancer cells and CTL activation in a MMP9-dependant manner. In the test with systemic administration of the conjugate to tumor-bearing mice, it revealed prominent tumor-homing effect and remarkably restrained tumor growth.
Conclusion: Our findings suggested that a tumor microenvironment-responsive polymeric conjugate with a foreign antigen can be an alternative and innovative methodology to elicit CTL-mediated immunological rejection of tumors. Most people including cancer patients already established several potent adaptive immunities against specific antigen they encountered before, such as influenza virus. Therefore, any kind of encountered pathogen-derived non-self antigen can be utilized in this strategy to awake these immunities out of hibernation.
Seok Ho Song– Ph. D. student, Sungkyunkwan University, Suwon-si, Kyonggi-do
Jung Min Shin– Sungkyunkwan University
Jae Hyung Park– Sungkyunkwan University, Kyonggi-do
Seokho Song– Mr, Sungkyunkwan University, Suwon-si, Gyeonggi-do