Biology subjects

Jordan, K. R.

Publications and source records attributed to Jordan, K. R..

3 recordsLinked to original sources

bioRxiv2021

SPF: A Spatial and Functional Data Analytic Approach to cell Imaging data

The tumor microenvironment (TME), which characterizes the tumor and its surroundings, plays a critical role in understanding cancer development and progression. Recent advances in imaging techniques enable researchers to study spatial structure of the TME at a single-cell level. Investigating spatial patterns and interactions of cell subtypes within the TME provides useful insights into how cells with different biological purposes behave, which may consequentially impact a subjects clinical outcomes. We utilize a class of well-known spatial summary statistics, the K-function and its variants, to explore inter-cell dependence as a function of distances between cells. Using techniques from functional data analysis, we introduce an approach to model the association between these summary spatial functions and subject-level outcomes, while controlling for other clinical scalar predictors such as age and disease stage. In particular, we leverage the additive functional Cox regression model (AFCM) to study the nonlinear impact of spatial interaction between tumor and stromal cells on overall survival in patients with non-small cell lung cancer, using multiplex immunohistochemistry (mIHC) data. The applicability of our approach is further validated using a publicly available Multiplexed Ion beam Imaging (MIBI) triple-negative breast cancer dataset.

bioinformatics↗

bioRxiv2020

Expression and T cell Regulatory Action of the PD-1 Immune Checkpoint in the Ovary and Fallopian Tube

The Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint has powerful immunomodulatory action, including in the context of cancer. PD-1 receptor activation by its ligands (PD-L1/2) is associated with downregulated immune response, and tumor cells can avoid surveillance via PD-1 and/or ligand expression. While receptor expression is largely limited to lymphoid, myeloid, and tumor cells, we show that membrane bound and soluble variants of PD-1 and ligands are also expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were highly enriched in exosome fractions in human follicular fluid at bioactive levels that can control T cell PD-1 activation. PD-1 checkpoint signaling may be involved in physiological ovarian functions including follicle, and ultimately, germline and embryo immune-privilege.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

The capacity of the ovarian cancer tumor microenvironment to integrate inflammation signaling conveys a shorter disease-free interval

Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is typically effective, but most patients will develop chemo-resistant disease. Mechanisms driving clinical chemo-response and -resistance in ovarian cancer are not well understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant platinum/taxane-based chemotherapy (NACT). NACT offers a window to profile pre-versus post-therapy tumor specimens, which we used to identify chemotherapy-induced changes to the tumor microenvironment. We hypothesized changes in the immune microenvironment correlate with tumor chemo-response and disease progression. We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient n=6). We measured mRNA levels of 770 genes (NanoString), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in additional pre-NACT ascites samples (n=39) by multiplex ELISA. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multi-spectral immunohistochemistry. In NanoString analyses, transcriptional profiles segregated based on pre- and post-NACT status. The most upregulated gene post-NACT was IL6 (17.1-fold, adjusted p = 0.045). RPPA data were highly concordant with mRNA, consistent with elevated immune infiltration. Elevated IL-6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString, RPPA, and cytokine studies identified an activated inflammatory signaling network and induced IL6 and IER3 (Immediate Early Response 3) post-NACT, associated with poor chemo-response and decreased time to recurrence. Taken together, multi-omic profiling of ovarian tumor samples before and after NACT provides unique insight into chemo-induced changes to the tumor and microenvironment. We integrated transcriptional, proteomic, and cytokine data and identified a novel IL-6/IER3 signaling axis through increased inflammatory signaling which may drive ovarian cancer chemo-resistance.

cancer biology↗