Abstract 173P
Background
Obesity is associated with chronic inflammation and elevated incidence and mortality from multiple cancer types, including colorectal cancer (CRC). We found that CRC progression is enhanced in diet induced obesity (DIO) mouse models. Obesity-induced metastasis showed significant enrichment in myeloid cells coinciding with a relative decrease in lymphoid populations. However, the functional contribution of these associations to CRC progression remains unknown. Here we define how obesity changes the tumor immune microenvironment (TIME) to alter disease outcome.
Methods
To model obesity-driven CRC progression, 5-week old wild-type male mice were enrolled on low fat (LF) or high fat (HF) isocaloric diet and injected with syngeneic CRC cell lines. To test the effect of myeloid populations, genetic and antibody-based approaches were used to deplete specific myeloid subsets. Primary and metastatic tumors were analyzed by histology and spectral flow cytometry to evaluate disease burden and accompanying immunological changes.
Results
Obesity was associated with a ∼20% reduction in lymphocytes in the TIME. T cells in particular were significantly excluded from the microenvironment and exhibited an exhausted phenotype. This effect was paired with a ∼50% increase in intratumoral myeloid cells in obese mice compared to lean mice. Targeting specific myeloid subsets in obese mice improved lymphocyte infiltration by ∼40%, rescued their exhaustion status, and reduced disease burden.
Conclusions
These data suggest the immunological consequences of obesity contribute to cancer progression through a bias toward myeloid populations, which suppress functional T cells to impair immune surveillance. Our findings provide insight into myeloid-targeted immunotherapies in obesity-associated CRC.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
CIHR, Rosalind and Morris Goodman Cancer Institute, Division of Experimental Medicine.
Disclosure
All authors have declared no conflicts of interest.
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