Immunogenic tumor cell death induced by chemoradiotherapy: molecular mechanisms and a clinical translation

Abstract

Chemoradiotherapy can induce immunogenic cell death, triggering danger signals such as high-mobility group box 1 protein, and resulting in T-cell immunity. This concept can potentially be harnessed for clinical therapy to enhance tumor-specific immunity. There is however limited information to translate this theory directly in a clinical setting. In this review, we will discuss and summarize molecular and cellular mechanisms underlying immunogenic tumor cell death induced by chemoradiotherapy, with emphasis on a clinical translation.

Figure 1

The abscopal effect in a relapsed lymphoma patient. An 81-year-old female had a relapsed lymphoma. Radiation therapy (total of 30.6 Gy in 17 fractions) was administered to the left hilar lymph node lesion (blue square). FDG-PET images (top and middle in panel a and b) and axial CT images (bottom in panel a and b) are shown. Blue squares indicate the irradiated field to the left hilar lymph node invasion; black arrows indicate the left parotid gland invasion (middle in panel a and b) and white arrows indicate the right hilar lymph node invasion (bottom in panel a and b). Panel a shows images before local radiotherapy. In panel b showing images at 8 months after local radiotherapy, the radiation-targeted left hilar lymphadenopathy and abnormal accumulation of FDG was disappeared (top). Furthermore, disease response outside of the irradiated field was seen with decreased left parotid gland (middle) and right hilar lymph node invasion (top and bottom)

Figure 2

Schematic representations of tumor antigen-specific T-cell responses in patients with ESCC receiving chemoradiotherapy. HMGB1, high-mobility group box 1 protein

Figure 3

Schematic representations of possible molecular machineries whereby TIM-3 on tumor-infiltrating DCs negatively regulate innate immune signals that would be activated by HMGB1–TLR4 interaction. HMGB1, high-mobility group box 1 protein; TIM-3, T-cell immunoglobulin- and mucin-domain-containing molecule; TLR, toll-like receptor