Type I Diabetes Mellitus impairs cytotoxic immunity through CEACAM5 upregulation in colorectal cancer : Exploring the intersection of autoimmune dysfunction and cancer progression: the role of NF-κB p65 in colorectal cancer.

Abstract

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.