Abstract:

Patients with locally advanced cancer or distant metastasis frequently receive prolonged treatment with chemotherapy and/or fractionated radiotherapy (RT). Despite the initial clinical response, treatment resistance frequently develops and cure in these patients is uncommon. Developments in radiotherapy technology allow for the use of high dose (or ablative) RT to target local tumors, with limited damage to the surrounding normal tissue. Although the current rationale of RT is based on direct cytotoxicity to cancer cells, we report that reduction of tumor burden following ablative RT depends largely on host T cell responses. Ablative RT dramatically increases T cell priming in draining lymphoid tissues, leading to reduction/eradication of the primary tumor or distant metastasis in a CD8+ T cell-dependent fashion. We further demonstrate that ablative RT-initiated immune responses and tumor reduction are abrogated by conventional fractionated RT or adjuvant chemotherapy, but greatly amplified by local immunotherapy.

However, the capacity of RT to link innate to adaptive immunity remains unclear. Endogenous type I interferon (IFN-?/?) signaling has been linked to the development of anti-tumor immune responses. Here, we show that ablative RT increases production of interferon-? (IFN-?) inside tumors. Indeed, the therapeutic effect of RT is diminished in IFN-?/? non-responsive hosts. Furthermore, responsiveness to IFN-?/? by hematopoietic cells is critical for RT-induced tumor reduction. Using adenoviral-induced expression of IFN-? to mimic RT, we demonstrate a preferential expansion of antigen-specific cells, increased antigen-specific lysis, and CD8 + T cell-dependent tumor reduction.

Our study reveals that ablative RT can trigger danger signaling and production of type I IFN, initiating a coordinated innate and adaptive immune attack against tumor cells. Furthermore, our study challenges the rationale for current radio/chemotherapy strategies and highlights the importance of immune activation in preventing tumor relapse. Our findings emphasize the need for new strategies that not only reduce tumor burden but also enhance the role of anti-tumor immunity.