Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling

Abstract

Metastatic prostate cancer (mPC) comprises a spectrum of diverse phenotypes. However, the extent of inter- and intra-tumor heterogeneity is not established. Here we use digital spatial profiling (DSP) technology to quantitate transcript and protein abundance in spatially-distinct regions of mPCs. By assessing multiple discrete areas across multiple metastases, we find a high level of intra-patient homogeneity with respect to tumor phenotype. However, there are notable exceptions including tumors comprised of regions with high and low androgen receptor (AR) and neuroendocrine activity. While the vast majority of metastases examined are devoid of significant inflammatory infiltrates and lack PD1, PD-L1 and CTLA4, the B7-H3/CD276 immune checkpoint protein is highly expressed, particularly in mPCs with high AR activity. Our results demonstrate the utility of DSP for accurately classifying tumor phenotype, assessing tumor heterogeneity, and identifying aspects of tumor biology involving the immunological composition of metastases.

A Personalized Genomics Approach of the Prostate Cancer

“…Figure 1 shows also the substantial differences among the three cancer nodules with respect to each of the three independent variables, indicating that the recognized tumor transcriptomic heterogeneity [ 34 , 35 , 36 ] does not stop at the expression levels of genes in the four regions. Tumor heterogeneity in the control of transcripts abundances and gene networking indicates distinct alterations of the cellular biological processes and remodeling of the functional pathways as illustrated below.…”

“…In recent years, highly cited papers documented that tumors have not only heterogeneous histology but also heterogeneous gene expression profiles [ 34 , 35 , 36 ] as proved also by us in a case of clear cell renal cell carcinoma [ 37 ]. If this is true within one tumor, what justifies comparing the average gene expression profiles in large groups of phenotypically similar but distinct cancer patients with healthy counterparts as reported by thousands of papers?…”

Targeting the spectrum of immune checkpoints in prostate cancer

“…Primary untreated prostate cancer exhibits remarkable homogeneity in infiltrating immune cell composition, with high relative abundance of follicular helper T cells, eosinophils, and mast cells [52]. In contrast, metastatic (and usually previously hormonally treated) prostate cancers are often described as 'immunologically cold' tumors with low densities of tumor-infiltrating lymphocytes (TIL) on the order of 100 CD8 + T cells per mm 2 [53][54][55]. As a point of comparison, metastatic melanomas tend to have TIL densities on the order of 1000 CD8+ cells per mm 2 , with higher baseline TIL density associating with greater responses to PD-1 blockade [56].…”

“…Among the B7 superfamily, B7-H3 (less commonly known as PD-L3) appears to be more highly expressed than PD-L1, PD-L2, and B7-H4 in prostate cancer, and its expression correlates with Gleason score, tumor stage, and castration-resistant metastatic disease, [53,125]. In a recent study of metastatic prostate cancer, up to 88% of the samples had a high expression of B7-H3, with expression correlating with AR expression [55]. The function of B7-H3 is poorly defined; it is unknown whether it can activate co-stimulatory pathways or coinhibitory pathways, or perhaps this may be contextdependent.…”

Transformational Role of Medical Imaging in (Radiation) Oncology

“…Tumor-extrinsic features of the extracellular matrix (ECM) and tumor microenvironment (TME) lead to dynamic interplay between epigenetically regulated phenotypes. Spatial heterogeneity in TME components across a tumor may reinforce intra-tumor heterogeneity, whereas global changes in TME between patients influences inter-tumor heterogeneity [ 16 ].…”