Anti-Cachexia Effect of Polymorphonuclear Myeloid-Derived Suppressor Cell Depletion Therapy is Not Present in Tumor-Bearing Mice Lacking T and B Cells

Authors

Hailey K. Gorman, University of New MexicoFollow
Jonathan SpechtFollow
Michael Deyhle, University of New Mexico - Main CampusFollow

Abstract

Polymorphonuclear (PMN) Myeloid-derived suppressor cells (MDSCs), are associated with poor cancer prognosis, partly due to their immunosuppressive effects on anti-cancer immunity. Cancer cachexia, characterized by debilitating skeletal muscle wasting, further reduces patient survival. Previously, antibody-mediated (anti-Ly6G) depletion of PMN-MDSCs attenuated skeletal muscle loss in mouse model of cancer cachexia. The mechanism by which PMN-MDSCs contribute to cachexia is unclear. Given the role that PMN-MDSCs play in supporting cancer disease progression depends on inhibiting anti-cancer adaptive immunity, we tested if the beneficial effects of PMN-MDSCs depletion on cachexia depend on the presence of adaptive immune cells. PURPOSE: We hypothesize that the anti-cachexia effect of the PMN-MDSC depletion therapy is dependent on the presence of the adaptive immune system. METHODS: Using wild type (WT) and RAG1 KO mice (lacking mature T and B cells), we investigated the involvement of the adaptive immune system on the anti-cachexia effect of PMN-MDSC depletion. Wild-type and control mice underwent surgery to receive either orthotopic injections of KPC-1245 murine pancreatic cancer cells or an equal volume of PBS, respectively. Starting on day 5 post-tumor cell injection, mice received intraperitoneal injections of either anti-Ly6G antibody or vehicle every three days. Mice were euthanized on day 14. Body mass was monitored daily. Tissue weights (including skeletal muscles, tumor, spleen) were measured at the study endpoint. Motor control was assessed by measuring latency to fall on a Rotarod device to evaluate the functional impact of muscle atrophy. RESULTS: Anti-Ly6G treatment attenuated body mass loss in wild-type tumor-bearing mice compared to controls. conversely, RAG1 knockout mice treated with anti-Ly6G had worsened weight loss and no significant preservation of muscle mass. Spleen weight responded differently between genotypes, suggesting distinct immunomodulatory effects. CONCLUSIONS: These findings indicate that the anti-cachexia effects of PMN-MDSC depletion are dependent on an intact adaptive immune system. Exacerbated cachexia observed in RAG1 knockout mice suggests a complex interplay between PMN-MDSCs, adaptive immunity, and muscle wasting.

Recommended Citation

Gorman, Hailey K.; Specht, Jonathan; and Deyhle, Michael (2024) "Anti-Cachexia Effect of Polymorphonuclear Myeloid-Derived Suppressor Cell Depletion Therapy is Not Present in Tumor-Bearing Mice Lacking T and B Cells," International Journal of Exercise Science: Conference Proceedings: Vol. 14: Iss. 4, Article 19.
Available at: https://digitalcommons.wku.edu/ijesab/vol14/iss4/19