Biology subjects

Park, J. C.

Publications and source records attributed to Park, J. C..

3 recordsLinked to original sources

bioRxiv2024

Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma

PurposeAdenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental DesignWe leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-{psi} or a STING agonist. ResultsmIF demonstrated that ACC tumors are immunologically cold, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-{psi} or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. ConclusionsLow/absent HLA/B2M expression may explain ACC tumors immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.

cancer biology↗

bioRxiv2024

Impact of PI3K pathway alterations on response to immune checkpoint inhibitors in HPV-negative head and neck squamous cell carcinoma

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K pathway) is a major intracellular regulatory pathway commonly involved in cancer survival, proliferation, migration, and metabolism. Activating mutations and amplifications of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are frequent genomic features of head and neck squamous cell carcinoma (HNSCC). A growing body of evidence suggests that dysregulation of the PI3K pathway suppresses the anti-tumor immune response, thereby enabling tumor immune evasion. We retrospectively analyzed clinicopathologic and genomic data of patients with recurrent or metastatic (R/M) HNSCC treated with immune checkpoint inhibitors (ICI). PI3K pathway alterations were found in 44% and were associated with poor clinical outcomes in the human papillomavirus-negative (HPV-ve) HNSCC patients. PIK3CA expression was found to be inversely correlated with immune gene expression, decreased T-cell infiltration, and reduced CD8 T-cell cytotoxic activity. The pharmacologic inhibition of the PI3K pathway induced an increase in key immune-responsive gene expression in PIK3CA-mutant HPV-ve HNSCC cells. These findings suggest that the PI3K pathway activation promotes immune suppressive phenotype, and playing a role in conferring resistance to immune checkpoint inhibitors in HPV-ve subset of HNSCC patients. HighlightsAlterations in PI3K pathway are associated with poor clinical outcomes in HPV-negative HNSCC patients treated with immune checkpoint therapy. PI3K pathway activation correlates to immune suppressive tumor microenvironment in HNSCC. Pharmacologic inhibition of PI3K induces the expression of interferon-gamma responsive and antigen presentation machinery genes in HNSCC.

cancer biology↗

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗