Besides exerting cytostatic or cytotoxic effects on tumor cells, some anti-cancer therapies (anthracyclines, oxaliplatin, X-Rays) could trigger an immunogenic cell death modality, releasing danger signals to alert immune system. We have shown that tumor-specific IFN- producing CD8+ T cells (Tc1) are mandatory for the success of chemotherapy to prevent tumor outgrowth. Priming of Tc1 response depends on IL-1β secretion by DC confronted with anthracycline-treated tumor cells releasing ATP. To identify the inflammatory components which link innate and cognate immune responses, we analyzed the influence of immunogenic chemotherapy on tumor microenvironment. We found an upregulated Th1- and Th17-related gene expression pattern in growth-retarded tumor after anthracycline treatment. By interfering with IFN- or IL-17A pathways, therapeutic effect of doxorubicin and oxaliplatin was abolished and dying tumor cell-based vaccine lost its efficacy to protect mice from live tumor cell rechallenge. Interestingly, we discovered that distinct subsets of T lymphocytes (V4+ and V6+) colonized tumors shortly after chemotherapy, where they proliferated and became the dominant IL-17 producers within tumor beds. In three tumor models treated with chemotherapy or radiotherapy, a strong correlation between the presence of IL-17-producing T ( T17) and IFN--producing CD8+ TIL (Tc1) was discovered. IL-17A signaling acts as upstream of IFN- since defect in IL-17RA led to complete loss of antigen specific Tc1 priming. The contribution of T17 cells (V4+ and V6+) to chemotherapy is critical as V4/6-/- mice showed reduced sensitivity to chemotherapy and vaccination. Also, tumor infiltrating T17 and Tc1 cells were reduced to basal level in this strain. IL-1β/IL-1R, but not IL-23/IL-23R, is pivotal for IL-17 production by T cells and the success of chemotherapy. Importantly, adoptive transfer of T cells could restore the efficacy of chemotherapy in IL-17A-/- mice and ameliorate the effect of chemotherapy in wild type host, provided that they retain the expression of IL-1R and IL-17A. Our research suggest a DC (IL-1β) → T cells (IL-17) → Tc1 (IFN-) immune axis triggered by chemotherapy-induced dying tumor cells, which is critical for the favorable therapeutic response. To boost the immune system, we try to combine immunogenic chemotherapy with tumor vaccine in the presence of TLR3 agonist Poly (A:U). This sequential combined therapy, which we named VCT, could significantly retard tumor growth or even completely eradicate tumor and establish long-term protection against rechallenge in highly tumorigenic models. To dissect the effect of Poly (A:U) on immune system and that on TLR3 expressing-tumor cells, we performed VCT treatment in nude mice, TRIF-/- mice and with TRIF-silencing tumors. Interestingly, our results suggested that anti-tumor effect of VCT required T cells and intact TRIF signaling pathway at the level of the host and that of tumor cells. Poly (A:U) treatment could induce high level of CCL5 and CXCL10 production from tumor cells both in vitro and in vivo, which could negatively and positively influence the therapeutic outcome. By uncoupling the effect of CCL5 from that of CXCL10, the VCT treatment can be ameliorated. Our study emphasizes that both tumor and host derived inflammatory factors participate in regulating anti-tumor response. We also highlight that therapeutic application of TLR agonists can be optimized through regulating the profile of chemokines and their downstream signaling events.
| Identifer | oai:union.ndltd.org:CCSD/oai:tel.archives-ouvertes.fr:tel-00636891 |
| Date | 28 June 2011 |
| Creators | Ma, Yuting |
| Publisher | Université Paris Sud - Paris XI |
| Source Sets | CCSD theses-EN-ligne, France |
| Language | English |
| Detected Language | English |
| Type | PhD thesis |
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