Toll-like receptor 4 and alarmin high-mobility-group box 1 are essential to activate immune system after chemotherapy and radiotherapy for cancers

Immunotherapy for cancer, such as for renal cell carcinoma, has been taken as one of therapy of choice for a long time. The article from Apetoh L. et al. in Nature Medicine provided a molecular perspective of this clinical phenomenon.

Stemming from the paper of Casares N. et al. on The Journal of Experimental Medicine in 2005, they tried to explored how tumor cell death can induce an antitumor immune response. They hypothesized toll-like receptors to mediate this response. The reason for this hypothesis was not specified, but I would do the same! By exposing bone marrow-derived dendritic cells (BM-DCs) to dying ovalbumin-expressing EG7 mouse thymoma cells treated with either oxaliplatin or radiation, they found toll-like receptor 4 (TLR4) is indispensible to this immune reaction.

Moreover, they found the ligand, too. Among a variety of endogenous ligands for TLR4, like heat-shock protein 60 (HSP60), heat-shock protein 70 (HSP70), oxidized LDL, surfactant protein A, hyaluronan breakdown products, fibronectin, beta-defesin-2, and alarmin high-mobility-group box 1 (HMGB1), HMGB1 stands out in the supernatants of dying ovalbumin-expressing EG7 mouse thymoma cells or CT26 colon cancer cells treated with radiation or doxorubicin. Further immunological approaches and siRNA knock-down experiments confirmed that HMGB1 is also indispensible to initiate the immune activity. This is also shown in dying MCA205 sarcoma cells.

The findings underscore the clinical observation that patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy or chemotherapy. These Asp299Gly TLR4 mutation did affect the binding of HMGB1 to TLR4.

However, I don't understand in this scenario, how cytotoxic T-lymphocytes work after the activation of toll-like receptor pathway. It is shown that HMGB1 is not presented on the cellular membrane, but in whole cell lysate or supernatant only. To make it short, what is the signal for those membrane is intact?

On the other hand, this article made me think of those autoimmune disease. Is this dying cell model relevant to the molecular mechanism of those autoimmune disease?

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Tags: Immunotherapy, Cancer therapy, chemotherapy, radiotherapy, radiation, toll-like receptor 4, TLR4, HMGB1, high-mobility-group box 1, alarmin, cancer, malignancy, autoimmune disease, molecular biology, molecular medicine, renal cell carcinoma, kidney cancer, colon carcinoma, colon cancer, breast cancer, antitumor, immune response, dendritic cell, bone marrow, heat-shock protein, HSP60, HSP70, oxaliplatin, doxorubicin, sarcoma, relapse, cytotoxic T cells, autoimmune disease, Medicine-Immunology, Medicine-Haematology, Medicine-Hematology, Medicine-Oncology, Medicine-Rheumatology, Medicine-Molecular Biology, Medicine-Microbiology, Medicine-Urology, Medicine-General Surgery, Medicine, Medical Science, Biomedical Science, Biological Science