Skeletal muscle in cancer: Exploration of the local immune environment and its associations to muscle mass in cancer

• Author / Creator

  Anoveros Barrera, Ana T

• Low muscle mass and muscle wasting are concerning issues as they are associated with poor outcomes and reduced survival in the oncological setting. Inflammation is a recognized contributor to disease-associated muscle loss; however, the biological characteristics of muscle tissue exhibiting aberrant muscle features such as low muscle mass or muscle wasting are not known in the cancer setting. . Immune cells are participants of the cycle of inflammation which have been associated with low muscle mass in a variety of cancer populations; however, there is limited knowledge on the immune environment of skeletal muscle during cancer. Lymphocyte and neutrophil tissue migration is suspected as relevant event occurring in the host as part of the response to cancer and it has been linked to cancer-induced tissue wasting. In the present study, we explored clinical and animal models to expand the knowledge on the involvement of immune cells within skeletal muscle in association with muscle mass during cancer.
  In a clinical model, we investigated the relationships between immune cells from the innate and adaptive response and muscle mass of a cancer population (n = 30, 91% gastrointestinal malignancies and 67%). Muscle fiber CSA was positively correlated (r = > 0.45; p = < 0.05) with total number of T cells, CD4, and CD8 T cells and CD11b+ granulocytes/phagocytes. Consistently, patients with a higher number of CD8 T cells had larger muscle fiber CSA and higher skeletal muscle index. Further exploration on gene-array data generated in a second identical patient cohort revealed inverse associations between CD8 T cell-related genes with key genes involved in muscle catabolic pathways: (Caspase 8), autophagy (Beclin 1), catabolic signaling (ACVR2B and ACVR1B receptors) and ubiquitin proteasome (FBXO32, FOXO4, MUL1 and TRIM63) (r = ≥ 0.5; p = <0.0001).
  In a preclinical cancer model, we explored the effect of cancer and chemotherapy treatment in lymphocyte and neutrophil migration into skeletal muscle. A global gene expression dataset was generated from skeletal muscle of a ward colorectal tumor-bearing rat model developed to study the effect of chemotherapy exposure (irinotecan/5- Fluorouracil) and which is known to exhibit mild muscle atrophy. Differential expression of genes encoding toll-like receptors (TLR5 and CD14), chemokines (CXCL14, CX3CL1 and CXCR4) and cellular adhesion molecules (SELE, ITGAD and ITGB2A) revealed the involvement of immune cell migration in muscle as part of the response to tumor burden, while chemotherapy exposure promoted the differential expression on additional genes encoding TLR-adaptor MAL/TIRAP and TLR-associated enzyme IRAK4, as well as chemokine ligand CCL6. Gene exploration with Ingenuity Pathway Analysis® resulted in the identification of three genes (ITGAD, ITGB2, CD6) encoding surface molecules exclusively expressed in lymphocytes and/or myeloid cells, providing initial evidence of their presence within skeletal muscle in tumor-bearing rodents, as well as chemotherapy exposed rodents.
  
  In conclusion, findings from clinical and preclinical models suggest an involvement of immune cells from innate and adaptive immune response with muscle mass in cancer. Lymphocyte and phagocyte tissue migration, which has been linked to muscle loss, is a relevant event occurring in muscle in response to cancer. In addition, exposure to chemotherapy influences the local immune environment of muscle and promotes upregulation of genes involved in immune cell migration; however, more studies are needed to understand its effect to repeated exposures. Further exploration is required to understand the dynamics of immune cells and skeletal muscle, and their implications in muscle mass in cancer. Overall the present work is an important contribution to the fields of skeletal muscle abnormalities in cancer, cancer cachexia and muscle disease.

• Subjects / Keywords

  • T cells
  • cancer
  • immune environment
  • muscle tissue
  • immune cells
  • skeletal muscle
  • inflammation
  • phagocytes
  • cancer cachexia

• Graduation date

  Spring 2020

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-wcf4-7d83

• License

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