Radiation-Induced CXCL16 Release by Breast Cancer Cells Attracts Effector T Cells

Abstract

Recruitment of effector T cells to inflamed peripheral tissues is regulated by chemokines and their receptors, but the factors regulating recruitment to tumors remain largely undefined. Ionizing radiation (IR) therapy is a common treatment modality for breast and other cancers. Used as a cytocidal agent for proliferating cancer cells, IR in combination with immunotherapy has been shown to promote immune-mediated tumor destruction in preclinical studies. In this study we demonstrate that IR markedly enhanced the secretion by mouse and human breast cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and plays an important role in their recruitment to sites of inflammation. Using a poorly immunogenic mouse model of breast cancer, we found that irradiation increased the migration of CD8+CXCR6+ activated T cells to tumors in vitro and in vivo. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression following treatment with local IR to the tumor and Abs blocking the negative regulator of T cell activation, CTLA-4. These results provide the first evidence that IR can induce the secretion by cancer cells of proinflammatory chemotactic factors that recruit antitumor effector T cells. The ability of IR to convert tumors into “inflamed” peripheral tissues could be exploited to overcome obstacles at the effector phase of the antitumor immune response and improve the therapeutic efficacy of immunotherapy.

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

“…38 Of interest, CCL2 and CXCL16 induced by CLL exosomes are important chemoattractants for macrophages and T cells, respectively. 63,64 CAF-derived factors are known to modulate immune cell functions, skewing T cells and myeloid cells into immunosuppressive and tumor-promoting Th2/M2-like phenotypes. CCL2, CXCL1, and hepatocyte growth factor (HGF) were found to be elevated in serum of CLL patients vs healthy donors (M. Seiffert, unpublished data, 2014), indicating high clinical relevance.…”

Chemokines in cancer related inflammation

“…In human glioma, colorectal, breast and renal cancer, tumors with high CXCL16 expression had slower progression and showed infiltration of CD4 and CD8 lymphocytes [53][54][55][56][57]. On the contrary in prostate cancer CXCL16 expression has been correlated with poor prognosis [58].…”

“…On the contrary in prostate cancer CXCL16 expression has been correlated with poor prognosis [58]. Interestingly, it has been reported that ionizing radiation therapy markedly enhanced CXCL16 secretion by mouse and human breast cancer cells, which recruited CXCR6+ effector cells [55].…”

Comparison of the therapeutic efficacy of 188Rhenium-liposomes and liposomal doxorubicin in a 4T1 murine orthotopic breast cancer model

“…Matsumura et al reported that radiotherapy improved the therapeutic efficacy of immunotherapy, by converting tumors into inflamed tissues (39,40). After exposure to ionizing radiation, enhanced production of pro-inflammatory chemokine CXCL16 was observed in 4T1 breast tumor cells, resulting in reduced tumor growth, in vitro and in vivo, by facilitating the effector phase of the antitumor immune response (39,40). In addition, Horton et al also demonstrated that Trastuzumab (Herceptin) enhanced the effectiveness of radiotherapy, by increasing radio-sensitivity, in breast cancer patients (36).…”