The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed. Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns. The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR(95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59(1.49-8.62)) associations of the tumour stroma fraction with survival. Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance. The Swedish Cancer Society, The Lions Cancer Foundation Uppsala, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P.O.Zetterling Foundation, and The Sjöberg Foundation, Sweden.

While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naïve CRC patients clustered into an ‘inflamed’ and a ‘desert’ group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046–0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment.

Metabolic processes are altered in cancer cells, which obtain advantages from this metabolic reprogramming in terms of energy production and synthesis of biomolecules that sustain their uncontrolle...

Studies have implied that fibroblasts may act as regulators of immune cells in the tumor microenvironment (TME). We investigated the clinical relevance of fibroblast activation protein (FAP) positive stroma in high-grade serous ovarian cancer (HGSC) in relation to CD8+ lymphocyte's infiltration. In a discovery cohort (N = 113) of HGSC, expression of FAP and CD8 in the TME was analyzed with immunohistochemistry. Results were correlated with overall survival (OS) and progression-free survival (PFS). The findings were validated in an independent cohort of HGSC (N = 121) and in public available datasets. High infiltration of CD8+ cells in the TME of HGSC was found to be associated with longer OS, as previously known. Increased expression of FAP was associated with shorter median PFS (11.4 vs. 18.6 months) in tumors with high density of CD8+ cells (HR 4.03, CI 95 % 1.38-11.72, p = 0.01). Similarly, in the validation cohort, high intensity of FAP in cases with high density of CD8+ cells was associated with shorter OS, 31.5 vs 76.9 months (HR 2.83; 95 % CI 1.17-6.86, p = 0.02). The results were consistent in multivariable analyses. The association between high FAP expression and poor outcome in high density CD8 HGSC was also confirmed in publicly available datasets. The TME infiltration of FAP-positive fibroblasts is associated with poor prognosis in HGSC with high CD8+ cells density. Targeting the FAP+ subset of fibroblasts may unlock the local immune-activation in the TME thus enhance the positive prognostic effect of T-cells in ovarian cancer.