Abstract
Numerous studies have shown that carbon ion radiotherapy (CIRT) induces anti-cancer immune responses in melanoma patients, yet the mechanism remains elusive. The abundance of myeloid-derived suppressor cells (MDSC) in the tumour microenvironment is associated with therapeutic efficacy and disease outcome. This study analysed the changes in the immune contexture in response to the carbon ion treatment. The murine melanoma B16, MelanA, and S91 tumour models were established in syngeneic immunocompetent mice. Then, the tumours were irradiated with carbon ion beams, and flow cytometry was utilised to observe the immune contexture changes in the bone marrow, peripheral blood, spleen, and tumours. The immune infiltrates in the tumour tissues were further assessed using haematoxylin/eosin staining and immunohistochemistry. The immunoblot detected the expression of proteins associated with the JAK/STAT signalling pathway. The secretion of immune-related cytokines was examined using ELISA. Compared to conventional radiotherapy, particle beams have distinct advantages in cancer therapy. Here, the use of carbon ion beams (5 GyE) for melanoma-bearing mice was found to reduce the population of MDSC in the bone marrow, peripheral blood, and spleen of the animals via a JAK2/STAT3-dependent mechanism. The percentage of CD3+, CD4+, CD8+ T cells, macrophages, and natural killer cells increased after radiation, resulting in reduced tumour growth and prolonged overall survival in the three different mouse models of melanoma. This study, therefore, substantiated that CIRT boosts anti-tumour immune responses via the inhibition of MDSC.
Highlights
Tumours often escape immunosurveillance by attracting the immunosuppressive cells into the tumour microenvironment (TME) that counteract the anti-tumour immune responses [1].Among the immunosuppressive population, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are most potent, significantly affecting immune escape and disease progression [2, 3]
Based on the existing knowledge of the long-term efficacy of heavy ion beams in the treatment of solid tumours, we tested whether carbon ion radiotherapy (CIRT) can decrease the abundance of the immunosuppressive cells
The amount of CD11b+GR1+ MDSC in the bone marrow (Fig. 1A) and peripheral blood were much lower (Fig. 1B) and significantly decreased in the spleen (Fig. 1C) and tumour (Fig. 1D) of carbon ion-irradiated animals compared to the X-ray irradiated and nonirradiated B16 melanoma-bearing mice
Summary
Tumours often escape immunosurveillance by attracting the immunosuppressive cells into the tumour microenvironment (TME) that counteract the anti-tumour immune responses [1]. Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) are most potent, significantly affecting immune escape and disease progression [2, 3]. MDSC downregulate the expression of the anti-tumour immune molecules, promoting the evasion immunosurveillance and enhancing the proliferation and differentiation of malignant cells. In animal models and clinical studies, reducing the number of MDSC significantly improved anti-cancer immune responses in tumour-bearing mice and therapeutic outcome in cancer patients [6, 12, 13]
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