Targeting Chromatin Effector Pygo2 to Enhance Immunotherapy in Prostate Cancer

Abstract

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling have emerging roles in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the anti-tumor efficacy of immunotherapies using immune checkpoint blockade, adoptive cell transfer, or myeloid-derived suppressor cell inhibitors. In human prostate cancer samples, Pygo2 expression was inversely correlated with CD8+ T cells. Our results highlight a promising path to improving immunotherapy with targeted therapy for lethal prostate cancer.

PYGO2 increases proliferation and migration capacities through critical signaling pathways in esophageal squamous cell carcinoma

“…It plays a role in various cellular processes, including stem cell self‐renewal, tissue homeostasis, and cancer progression. [ 5,9–13 ] CD markers are markers of cancer cells. CD133, with a molecular weight of 120 kDa, is one of the best indicators for identifying cancer stem cells.…”

“…It plays a role in various cellular processes, including stem cell self-renewal, tissue homeostasis, and cancer progression. [5,[9][10][11][12][13] CD markers are markers of cancer cells.…”