{
  "abstract": "Background The global population is becoming increasingly obese and skewing significantly older. Both obesity and aging increase the risk and mortality of cancer. It is critical to understand the immune response to cancer in these contexts to improve therapeutic patient outcomes. We and others have shown that obesity increases tumor growth and impairs anti-tumor immunity in mice and humans. Aging also impairs the cytotoxic CD8+ T cell response. However, the mechanisms that regulate cytotoxic CD8+ T cell function in obesity and aging are not fully understood. In cancer, CD8+ T cells become terminally exhausted, a differentiation state where cells lose effector function, renewal capacity, and can no longer control tumor growth. A subset of exhausted cells, progenitor exhausted cells, retain their renewal capacity and are the responding population to anti-PD1 therapy. Currently it is unknown if obesity and aging lead to the same state of CD8+ T cell dysfunction in the tumor and how this affects response to checkpoint blockade.Methods To determine the differences in the CD8+ T cell states between aging and obesity, we isolated CD8+ T cells from MC38 colorectal tumors in young lean mice (fed standard fat diet), young obese mice (fed high fat diet), and old lean mice (fed standard fat diet). Old mice were 75 weeks old at sacrifice, similar to a 65-year-old human, while young mice were 20 weeks old, similar to a 25-year-old human. We performed both single cell RNA sequencing and ATAC sequencing on the same CD8+ T cells. Analysis was performed to determine the T cell differentiation states as well as the number and regions of open chromatin in each group. We also performed flow cytometric analysis of tumors and tumor draining lymph nodes to confirm our findings.Results We found significant differences in the populations of CD8+ T cells present in obese mice compared to aged. We observed an increase in progenitor exhausted CD8+ T cells in obese but not aged mice. We also found significant differences in chromatin accessibility in the obese and the aged groups.Conclusions Together these data suggest that the populations of cytotoxic CD8+ T cells in obese and aged tumors are different. While obesity and aging both contribute to reduced cytotoxic CD8+ T cell response in the tumor, this may occur through separate pathways that lead to altered differentiation states. These data may have implications for treatment strategies in obese and aged populations.Ethics Approval This study was performed under the authorization of the IACUC committee at Princeton University (protocol #3169).",
  "authors": [
    {
      "affiliations": [
        "Princeton University, Princeton, NJ, USA",
        "Ludwig Princeton Branch, Princeton, NJ, USA"
      ],
      "name": "Kristin DePeaux"
    },
    {
      "affiliations": [
        "Princeton University, Princeton, NJ, USA",
        "Ludwig Princeton Branch, Princeton, NJ, USA",
        "Lewis Sigler Institute of Integrative Genomics, Princeton, NJ, USA"
      ],
      "name": "Zhiyue Zhang"
    },
    {
      "affiliations": [
        "Ludwig Princeton Branch, Princeton, NJ, USA"
      ],
      "name": "Brittany Bamonte"
    },
    {
      "affiliations": [
        "Princeton University, Princeton, NJ, USA",
        "Ludwig Princeton Branch, Princeton, NJ, USA"
      ],
      "name": "Nicolo Bancaro"
    },
    {
      "affiliations": [
        "Princeton University, Princeton, NJ, USA",
        "Lewis Sigler Institute of Integrative Genomics, Princeton, NJ, USA"
      ],
      "name": "Yuri Pritykin"
    },
    {
      "affiliations": [
        "Princeton University, Princeton, NJ, USA",
        "Ludwig Princeton Branch, Princeton, NJ, USA"
      ],
      "name": "Lydia Lynch"
    }
  ],
  "title": "821 Obesity and aging yield distinct CD8+ T cell differentiation patterns in the tumor microenvironment",
  "uid": "83652138-786b-5ac5-8a3b-b405f0d55706"
}