DP1 receptor signaling in aging-associated immune dysfunction in lung metastases PI: Jian Zheng

Recent studies from our laboratory revealed that age-related anti-viral immune dysfunction in the respiratory tract is driven by the increased expression of an inducible phospholipase A2 group IID (PLA 2G2D) enzyme and the prostaglandin D 2 receptor, DP1. Specifically, we discovered that age-related mortality in SARs-CoV2-infected mice were largely reversed in both PLA2G2D-/- and DP1 -/- mice as a consequence of enhanced lung dendritic cell (DC) mediated anti-viral-specific T cell responses. These survival benefits were subsequently confirmed in mice treated with a highly specific DP1 receptor antagonist, Asapiprant, which is currently being tested in phase II clinical trials. In our new preliminary studies, we have confirmed this age-related immune dysfunction pathway also exists in metastatic lung tumor-bearing mice. Specifically, we have found that PLA2G2D or DP1 deficiency, very effectively restricts the growth of melanoma lung metastasis in a manner that correlates with a substantial early enrichment of -T cells. In this phase 2 CCII COBRE project, we hypothesize that PLA2G2D/PGD2-DP1 signaling contributes to primary and metastatic tumor growth in the lung and acts by inhibiting age-associated inflammasome activation in lung DCs. To test this hypothesis, we will: 1) Determine the mechanisms and signaling effectors underlying PLA 2G2D/PGD2-DP1 signaling in lung DCs from aged, tumor-bearing mice, and 2) Investigate the potential of the DP1-targeting small molecule, Asapiprant, as a potential mono-immunotherapy in treating clinically relevant lung primary and metastatic disease models. Finally, these studies will evaluate whether DP1 targeting in immune checkpoint blockade (ICB) resistant implantable and spontaneous tumor models is sufficient to reduce resistance/increase efficacy in combination with anti-PD-1.