Despite significant changes in the clinical and histologic diagnosis of prostate cancer, the Gleason grading system remains one of the most powerful prognostic predictors in prostate cancer. The correct diagnosis and grading of prostate cancer is crucial for a patient’s prognosis and therapeutic options. However, this system has undergone significant revisions and continues to have deficiencies that can potentially impact patient care. We describe the current state of grading prostate cancer, focusing on the current guidelines for the Gleason grading system and recent changes from the 2014 International Society of Urological Pathology Consensus Conference on Gleason Grading of Prostatic Carcinoma. We also explore the limitations of the current Gleason grading system and present a validated alternative to the Gleason score. The new grading system initially described in 2013 in a study from Johns Hopkins Hospital and then validated in a multi-institutional study, includes five distinct Grade Groups based on the modified Gleason score groups. Grade Group 1 = Gleason score ≤6, Grade Group 2 = Gleason score 3 + 4 = 7, Grade Group 3 = Gleason score 4 + 3 = 7, Grade Group 4 = Gleason score 8, Grade Group 5 = Gleason scores 9 and 10. As this new grading system is simpler and more accurately reflects prostate cancer biology, it is recommended by the World Health Organization (WHO) to be used in conjunction with Gleason grading.

Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body type, we used prostate-specific Pten knockout mice as a prostate cancer model to investigate whether there is a gut microbiota–mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer–bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including Rikenellaceae and Clostridiales, inhibited prostate cancer cell proliferation, and reduced prostate Igf1 expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1 in vitro. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. Significance: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.

Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal carcinoma (IDC), is an aggressive histological subtype that is associated with progression to lethal disease. To delineate the molecular and cellular underpinnings of ICC/IDC aggressiveness, this study examines paired ICC/IDC and benign prostate surgical samples by single-cell RNA-sequencing, TCR sequencing, and histology. ICC/IDC cancer cells express genes associated with metastasis and targets with potential for therapeutic intervention. Pathway analyses and ligand/receptor status model cellular interactions among ICC/IDC and the tumor microenvironment (TME) including JAG1/NOTCH. The ICC/IDC TME is hallmarked by increased angiogenesis and immunosuppressive fibroblasts (CTHRC1⁺ASPN⁺FAP⁺ENG⁺) along with fewer T cells, elevated T cell dysfunction, and increased C1QB⁺TREM2⁺APOE⁺-M2 macrophages. These findings support that cancer cell intrinsic pathways and a complex immunosuppressive TME contribute to the aggressive phenotype of ICC/IDC. These data highlight potential therapeutic opportunities to restore immune signaling in patients with ICC/IDC that may afford better outcomes.

Background The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. Methods We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. Results The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. Conclusions Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence.