p21 loss in CD4+ T cells impedes the antitumor immune response against colorectal cancer

p21 activation is crucial for initiating cellular senescence within the DNA damage response (DDR). Its role is especially important during colorectal cancer (CRC) development, where high p21 expression has been correlated with increased overall survival of patients. p21 is also expressed in cells of the adaptive immune system, such as CD4+ T cells. CD4+ T cells are key players during CRC development due to their cytotoxic function as well as their ability to activate various other immune cell subtypes. The functional role of p21 in CD4+ T cells within the antitumor immune response against colorectal cancer has not yet been investigated.

To study how p21 activation in CD4+ T cells impacts CRC development, the in vivo MC38 orthotopic model was employed in Rag-/- mice injected with B6/J or Cdkn1a-/- CD4+ T cells. The role of p21 deletion on CD4+ T cell effector function was studied using in vitro models as well. Last, the expression of p21 in CD4+ T cells was evaluated in human CRC samples and correlated to cancer stage.

p21 deletion in CD4+ T cells led to increased tumor growth in Rag-/- mice injected with p21-/- CD4+ T cells compared to those that got B6/J CD4+ T cells. Tumor evaluation via immunohistochemistry revealed significantly less tumor cell death in mice that received p21-deficient CD4+ T cells compared to controls. These mice also had a significant decrease in IFNγ production of tumor-infiltrating immune cells. This effect was accompanied by a significant decrease in the relative numbers of Th1 cells at the tumor site. Furthermore, p21-/- Th1 cells showed an accelerated exhausted phenotype compared to B6/J Th1 cells. In vitro Th1 polarization of p21-/- CD4+ T cells also resulted in significant less IFNγ production and accumulation of exhausted effector/effector memory T cells that do not express CD27/CD28 co-stimulatory molecules. Finally, p21 expression in CD4+ T cells in human CRC samples was negatively correlated with cancer stage.

In conclusion, p21 loss in CD4+ T cells impedes Th1 polarization and leads to cytotoxic T cell exhaustion and therefore immune escape in colorectal cancer. These data shed light on p21’s function in maintaining CD4+ T cell effector function within the antitumor immune response against CRC.

Publication History

Article published online:
07 September 2021