Background

Periostin is an important extracellular matrix protein involved in cell development and adhesion. Previously, we identified periostin to be up-regulated in aggressive prostate cancer (CaP) using quantitative glycoproteomics and mass spectrometry. The expression of periostin was further evaluated in primary radical prostatectomy (RP) prostate tumors and adjacent non-tumorous prostate tissues using immunohistochemistry (IHC). Our IHC results revealed a low background periostin levels in the adjacent non-tumorous prostate tissues, but overexpressed periostin levels in the peritumoral stroma of primary CaP tumors.

Methods

In this study, periostin expression in CaP was further examined on multiple tissue microarrays (TMAs), which were conducted in four laboratories. To achieve consistent staining, all TMAs were stained with same protocol and scored by same image computation tool to determine the total periostin staining intensities. The TMAs were further scored by pathologists to characterize the stromal staining and epithelial staining.

Results

The periostin staining was observed mainly in peritumoral stromal cells and in some cases in tumor epithelial cells though the stronger staining was found in peritumoral stromal cells. Both periostin stromal staining and epithelial staining can differentiate BPH from CaP including low grade CaP (Gleason score ≤6), with significant p-value of 2.2e-16 and 0.001, respectively. Periostin epithelial staining differentiated PIN from low grade CaP (Gleason score ≤6) (p=0.001), while periostin stromal staining differentiated low grade Cap (Gleason score ≤6) from high grade Cap (Gleason score ≤6) (p=1.7e-05). In addition, a positive correlation between total periostin staining and Gleason score was observed (r=0.87, p=0.002).

Conclusions

The results showed that periostin staining was positively correlated with increasing Gleason score and the aggressiveness of prostate disease.

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR.See related commentary by Yang, p. 250This article is highlighted in the In This Issue feature, p. 235.