Alternative Activation of p38 in Infiltrating T Cells Promotes PDAC

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor that is promoted by cytokines and chemokines from the fibro-inflammatory microenvironment. One source of these cytokines is infiltrating T cells, which release cytokines as a result of alternative activation of p38 MAPK via phosphorylation of Y323 downstream of T-cell receptor (TCR) signaling. Due to the tumor-promoting effects of these cytokines, their selective manipulation represents a possible PDAC therapy, prompting Alam, Gaida, and colleagues to investigate the role of alternative p38 activation in 192 human PDAC tumors. There was no difference in total CD3⁺ T-cell infiltration among the tumors; however, tumors with increased accumulation of phosphorylated Y323⁺ (pY323⁺) tumor-infiltrating lymphocytes (TIL) had more CD4⁺ T cells producing proinflammatory cytokines and were associated with a poorer prognosis. In a mouse xenograft model of PDAC in which Y323 was mutated to abolish TCR-induced p38 activity (DKI mice), tumors were smaller than controls and exhibited less TNFα production by CD4⁺ TILs, resulting in reduced expression of Ccl2 and Vegf. Additionally, in a genetic mouse model of PDAC development, adoptive transfer of DKI bone marrow prolonged survival, indicating that the p38 alternative pathway in CD4 T cells promotes PDAC progression through the inhibition of tumor-promoting cytokine production. Treatment with a membrane-permeable peptide derived from growth arrest and DNA damage–inducible α (GADD45α), a selective inhibitor of the p38 alternative pathway, suppressed T-cell proliferation and function, decreased proinflammatory cytokine production by CD4⁺ TILs, and reduced tumor growth and vascularization in PDAC xenografts and genetic mouse models without toxicity. These findings highlight the importance of the p38 alternative pathway in PDAC TILs, and suggest that its selective inhibition may reduce PDAC tumor progression in patients with high levels of p38 pY323⁺ TILs.

Alam SM, Gaida MM, Bergmann F, Lasitschka F, Giese T, Giese NA, et al. Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. Nat Med 2015 Oct 19 [Epub ahead of print].