The complex heterogeneity of immune cell signatures across wasting tissues with C26 and 5-fluorouracil-induced cachexia

• Published in: American Journal of Physiology: Cell Physiology Vol. 326; no. 2; pp. C606 - C621
• Main Authors: VanderVeen, Brandon N, Cardaci, Thomas D, Bullard, Brooke M, Huss, Alexander R, McDonald, Sierra J, Muhammed, Ahmed D, Kubinak, Jason L, Fan, Daping, Murphy, E Angela
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2024
• Subjects: 5-Fluorouracil; Adipose tissue; Animals; Antineoplastic Agents - pharmacology; Body weight loss; Cachexia; Cachexia - metabolism; Cancer; CD11b antigen; CD11c antigen; Chemotherapy; Cytotoxicity; Dendritic cells; Flow cytometry; Fluorouracil - adverse effects; Inflammation; Lymphocytes B; Macrophages; Metastases; Mice; Muscle, Skeletal - metabolism; Muscular Atrophy - pathology; Myeloid cells; Skeletal muscle; Therapeutic targets; Tumors; adipose tissue; macrophages; cancer; skeletal muscle; chemotherapy
• ISSN: 0363-6143; 1522-1563; 1522-1563
• DOI: 10.1152/ajpcell.00548.2023

Immune cell-driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy-induced cachexia. CD2F1 mice were given 10 C26 cells, followed by five doses of 5-fluorouracil (5FU; 30 mg/kg LM, ip) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. Although 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26 + 5FU. C26 increased CD11b Ly6g and CD11b Ly6c inflammatory myeloid cells in SKM and AT; however, both populations were reduced with C26 + 5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26 + 5FU. C26 + 5FU increased SKM CD11b CD11c dendritic cells, CD11b NK1.1 NK-cells, and CD11b B220 B-cells, and reduced Ly6c CX3CR1 CD206 CD163 CD11c MHCII infiltrated macrophages and other CD11b Ly6c myeloid cells compared with C26. Both C26 and C26 + 5FU had elevated CD11b F480 CD206 MHCII or more specifically Ly6c CX3CR1 CD206 CD163 CD11c MHCII profibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, profibrotic cells and muscle inflammatory/atrophic signaling appear consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets. Despite being an immune-driven condition, our understanding of skeletal muscle and adipose tissue immune cells with cachexia is limited. Here, we identified immune cell populations in tumors, skeletal muscle, and adipose tissue in C26 tumor-bearing mice with/without 5-fluorouracil (5FU). C26 and C26 + 5FU had increased skeletal muscle profibrotic macrophages, but 5FU reduced inflammatory myeloid cells without sparing mass. Tumor presence and chemotherapy have contrasting effects on certain immune cells, which appeared not necessary for wasting.