Th178 - The CDKN2A Deletion Influences the Establishment of the Tumor Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

The immune TME of pancreatic ductal adenocarcinoma (PDAC) is heterogeneous between patients but it is well established that poor T cell infiltration and high frequency of immunosuppressive cells affect the prognosis of PDAC. Since CDKN2A deletion in tumor cells participates to the immunomodulation in cancer we sought to investigate its role in the establishment of the tumoral immune microenvironment of PDAC.

We injected into the pancreas of healthy mice two murine cell lines of PDAC: KPC cells or KPC carrying CDK2NA deletion (KPC-CDKN2A). Tumor infiltrated lymphocytes (TILs) were analyzed by flow cytometry to compare immune populations between the two mice models of PDAC. KPC-CDKN2A tumors were characterized by a lower proportion of CD8⁺ T cells and a higher proportion of regulatory T cells (CD4+Foxp3+). T cells into KPC-CDKN2A tumors harbored an exhausted phenotype (higher PD1+/CTL4+%), while Treg were more activated (CD25+/TNFR2+%). CDKN2A is a gene locus encoding for the tumor suppressor p14/p16 proteins, when deleted the checkpoint is bypassed and CDK4/6 are activated. Administration of a chemical inhibitor of CDK4/6 in KPC-CDKN2A tumor bearing mice impaired tumor growth. CD8+ T cells infiltration increased and TIGIT expression on TILs decreased in treated mice.

In conclusion, CDKN2A deletion seemed to promote infiltration of immunosuppressive cells and exhaustion of T cells in the TME. Restoring CDKN2A downstream pathways promoted CD8+ T cells infiltration. Studying the impact of CDKN2A deletion on the tumor immune microenvironment will allow improving therapeutic approaches and understanding the cause of immune infiltration heterogeneity in patients.