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dc.contributor.authorDuong, L.
dc.contributor.authorRadley-Crabb, H.
dc.contributor.authorGardner, J.
dc.contributor.authorTomay, F.
dc.contributor.authorDye, D.
dc.contributor.authorGrounds, M.
dc.contributor.authorPixley, F.
dc.contributor.authorNelson, Delia
dc.contributor.authorJackaman, Connie
dc.date.accessioned2019-02-19T04:16:38Z
dc.date.available2019-02-19T04:16:38Z
dc.date.created2019-02-19T03:58:11Z
dc.date.issued2018
dc.identifier.citationDuong, L. and Radley-Crabb, H. and Gardner, J. and Tomay, F. and Dye, D. and Grounds, M. and Pixley, F. et al. 2018. Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia. Frontiers in Genetics. 9: Article ID 526.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/74350
dc.identifier.doi10.3389/fgene.2018.00526
dc.description.abstract

Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. The immune system plays a critical role in the effectiveness of many anticancer therapies in young hosts via tumor-specific T cells. However, immunosuppressive macrophages can constitute up to 50% of the tumor burden and impair anti-tumor T cell activity. Altered macrophage phenotype and function during aging may further impact anti-tumor T cell responses. Yet, the impact of macrophages on anti-tumor T cell responses and immunotherapy in the elderly is unknown. Therefore, we examined macrophages and their interaction with T cells in young (3 months) and elderly (20– 24 months) AE17 mesothelioma-bearing female C57BL/6J mice during tumor growth. Mesothelioma tumors grew faster in elderly compared with young mice, and this corresponded with an increase in tumor-associated macrophages. During healthy aging, macrophages increase in bone marrow and spleens suggesting that these sites have an increased potential to supply cancer-promoting macrophages. Interestingly, in tumor-bearing mice, bone marrow macrophages increased proliferation whilst splenic macrophages had reduced proliferation in elderly compared with young mice, and macrophage depletion using the F4/80 antibody slowed tumor growth in young and elderly mice. We also examined responses to treatment with intra-tumoral IL-2/antiCD40 antibody immunotherapy and found it was less effective in elderly (38% tumor regression) compared to young mice (90% regression). Tumor-bearing elderly mice decreased in vivo anti-tumor cytotoxic T cell activity in tumor draining lymph nodes and spleens. Depletion of macrophages using F4/80 antibody in elderly, but not young mice, improved IL-2/anti-CD40 immunotherapy up to 78% tumor regression. Macrophage depletion also increased in vivo anti-tumor T cell activity in elderly, but not young mice. All the tumor-bearing elderly (but not young) mice had decreased body weight (i.e., exhibited cachexia), which was greatly exacerbated by immunotherapy; whereas macrophage depletion prevented this immunotherapy-induced cachexia. These studies strongly indicate that age-related changes in macrophages play a key role in driving cancer cachexia in the elderly, particularly during immunotherapy, and sabotage elderly anti-tumor immune responses.

dc.titleMacrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia
dc.typeJournal Article
dcterms.source.volume9
dcterms.source.issn1664-8021
dcterms.source.titleFrontiers in Genetics
curtin.departmentSchool of Pharmacy and Biomedical Sciences
curtin.accessStatusOpen access


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