Induction of immunogenic cell death of tumors by newly synthesized heterocyclic quinone derivative

Abstract

Many cancer types are serious diseases causing mortality, and new therapeutics with improved efficacy and safety are required. Immuno-(cell)-therapy is considered as one of the promising therapeutic strategies for curing intractable cancer. In this study, we tested R2016, a newly developed heterocyclic quinone derivative, for induction of immunogenic tumor cell death and as a possible novel immunochemotherapeutic. We studied the anti-cancer effects of R2016 against LLC, a lung cancer cell line and B16F10, a melanoma cell line. LLC (non-immunogenic) and B16F10 (immunogenic) cells were killed by R2016 in dose-dependent manner. R2016 reduced the viability of both LLC and B16F10 tumor cells by inducing apoptosis and necrosis, while it demonstrated no cytotoxicity against normal splenocytes. Expression of immunogenic death markers on the cell surface of R2016 treated tumor cells including calreticulin (CRT) and heat shock proteins (HSPs) was increased along with the induction of their genes. Increased CRT expression correlated with dendritic cell (DC) uptake of dying tumor cells: the proportion of CRT+CD11c+cells was increased in the R2016-treated group. The gene transcription of Calr3, Hspb1, and Tnfaip6, which are related to immunogenicity induction of dead cells, was up-regulated in the R2016 treated tumor cells. On the other hand, ANGPT1, FGF7, and URGCP gene levels were down-regulated by R2016 treatment. This data suggests that R2016 induced immunogenic tumor cell death, and suggests R2016 as an effective anti-tumor immunochemotherapeutic modality.

Nanoparticle-Mediated Remodeling of the Tumor Microenvironment to Enhance Immunotherapy

“…Each ssRNA discovered raised a slightly different immune response, giving researchers the ability to tune therapy to the needs of the tumor. 146 However, ssRNA would most likely need to be protected through a nanoformulation to be delivered safely to the tumor. This is one of the promises of nanomedicine: making administration of therapies more effective and safer for patients.…”

“…Only a subset of these have been used as ICD inducers in nanoformulations; most often, they are encapsulated and administered at therapeutic, cytotoxic doses. The interest in ICD as a cancer therapy has even resulted in the synthesis of novel drugs specifically for inducing ICD in cancer cells while remaining safe for healthy cells, like R2016 . In addition, photodynamic therapy, radiotherapy, and some ultraviolet radiation have been shown to induce ICD. − Nanomaterials like gold nanoparticles are especially valuable for ICD induction because they can enhance photodynamic therapy and radiotherapy intrinsically.…”

“…For example, recent research has shown that single-stranded RNA is able to bind PRRs and induce immunogenic cell death and robust antitumor responses. Each ssRNA discovered raised a slightly different immune response, giving researchers the ability to tune therapy to the needs of the tumor . However, ssRNA would most likely need to be protected through a nanoformulation to be delivered safely to the tumor.…”

Critical role of immunogenic cell death in cancer therapy

“…There is an urgent need to have a systemic survey of currently available anticancer agents to elicit the ICD in human cancer cells of different origins. Furthermore, it is important to identify novel agents that could elicit ICD or convert the non-immunogenic cell death into a bona fide ICD [8]. In addition, together with ICD, combination therapy including checkpoint blockers has the high probability to achieve more efficient therapeutic effects in clinical settings [6].…”

“…In addition, together with ICD, combination therapy including checkpoint blockers has the high probability to achieve more efficient therapeutic effects in clinical settings [6]. In this effort, nanoparticle-based immunotherapeutic strategies for the treatment of cancer, serving as antigen/adjuvant delivery vehicles and their combinations with chemotherapeutics, could further facilitate the development of the field [8][9][10].…”