CELL CYCLE REGULATION VIA P21 PATHWAY MEDIATES CD4+ T CELL EXHAUSTION DURING ANTI-TUMOR RESPONSE IN COLORECTAL CANCER

Colorectal cancer (CRC) remains one of the most common types of cancers worldwide. A multitude of genetic changes contributes to the initiation and progression of CRC. Amongst all, suppression of cell cycle inhibitory pathways, like p53/p21 and p16/pRb, are known to induce cancer progression. Furthermore, the immune system, and especially CD4+ T cells, can also contribute to CRC development. Here, we aim to evaluate how changes in cell cycle regulation via p21 affect the response of CD4+ T cells to CRC.
In vivo orthotopic MC38 tumor models and in vitro co-culture models were used to understand the response of p21-deficient CD4+ T cells to CRC. Furthermore, tumor tissue samples from patients were used for assessing p21 expression in CD4+ T cells.
p21 expression was observed in both murine and human CRC tissue samples. When Rag1-/- mice reconstituted with p21-/- CD4+ T cells were exposed to MC38 orthotopic model, we observed that they developed significantly larger tumors in comparison to the control mice. In human CRC tissue samples, low p21 expression in CD4+ T cells correlated with decreased cancer-free survival compared to those who had high p21. Functionally, mice that received p21-deficient CD4+ T cells showed significantly reduced IFNγ production and relative numbers of Tbet+ T cells in the TME, resulting in decreased tumor cell death. Most interesting, p21-/- Tbet cells found at the tumor site also showed significant loss of co-stimulatory molecules CD27/CD28 and developed into effector/effector memory cells, leading to an exhausted phenotype. Using Palbociclib, a CDK4/6 inhibitor, we were able to restore the lost function of p21 in CD4+ T cells, therefore reversing the phenotype in murine in vivo and in vitro models.
In conclusion, p21 plays an important role in mediating anti-tumor responses and exhaustion of CD4+ T cells. Targeting cell cycle downstream molecules using commercially available inhibitors such as Palbociclib might offer novel therapeutic strategies in CRC.