Redirecting dendritic cells and macrophages towards tumor rejection

Guiducci, Cristiana (2005). Redirecting dendritic cells and macrophages towards tumor rejection. PhD thesis The Open University.



The liver expressed chemokine CCL16/LEC exerts chemotactic activity on human monocytes and lymphocytes and is also active on murine cells. An adenovirus encoding the chemokine CCL16 was used to test whether this chemokine might inhibit pre-existing tumors in mice. AdCCL16, but not control empty vector, when injected in established TSA mammary carcinoma, significantly delayed tumor growth. Immunohistochemistry revealed accumulation at tumor site of CD4+ and CD8+ T cells, macrophages, and dendritic cells (DC) the latter being also enriched in draining lymph nodes. Despite the robust and rapid immune response triggered by intratumoral injection of AdCCL16, the lesions were not completely rejected. However the same treatment given before surgical excision of primary lesions prevented metastatic spread and cured 63% of mice bearing the 4T1 mammary adenocarcinoma. The finding of an hostile tumor microenvironment preventing innate immunity explains the weak effect on the primary tumor. As CCL16 promotes accumulation of macrophages and DC at the site of pre-established tumor nodules this treatment was combined with the TLR9 ligand CpG and with anti-interleukin 10-receptor (IL10R) antibody to contrast the local tumor-induced immunosuppression. CpG plus anti- IL10R promptly switched M2 infiltrating macrophages to Ml that, triggering a strong innate response, debulked large tumors within 16 hrs. Tumor infiltrating DC matured and migrated in parallel with the onset of the innate response, allowing the initiation of adaptive immunity before the diffuse hemorrhagic necrosis halted the communication between tumor and draining lymph node. Treatment of B6>CXB6 chimeras implanted with BALB/c tumors induced an efficient innate response but not CTL-mediated tumor lysis; in these mice tumor rejection did not exceed 25%. The requirement of CD4 help for an effective CTL induction was shown in CD40KO, as well as in mice depleted for CD4 T cells during the priming rather than the effector phase. Together the data describe the critical requirements for the immunological rejection of large tumors: a hemorrhagic necrosis initiated by activated Ml macrophages and a concomitant DC-migration to DLN for subsequent CTL priming and clearing of any tumor remnants.

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