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Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies.

Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G - Oncotarget (2015)

Bottom Line: Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts.Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies.Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.

No MeSH data available.


Related in: MedlinePlus

Variability of metagene correlations, upon treatment response in breast cancerA. Flow chart for producing B & C. (B & C) Metagene correlations, when they are significantly different upon treatment response, B. for immune metagenes, C. for correlations between immune metagenes and ER-stress (C.1), lysosome (C.2), autophagy (C.3). Heads of arrow represent correlations for responsive tumors, tails of arrow represent correlation for non-responsive tumors. P-values were associated to the combination of correlation difference, as delineated in A. Colors represent different datasets. On the left, details of metagene are plotted, for ER-stress, lysosomes and autophagy (the name of a metagene is defined by its most representative gene).
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Figure 7: Variability of metagene correlations, upon treatment response in breast cancerA. Flow chart for producing B & C. (B & C) Metagene correlations, when they are significantly different upon treatment response, B. for immune metagenes, C. for correlations between immune metagenes and ER-stress (C.1), lysosome (C.2), autophagy (C.3). Heads of arrow represent correlations for responsive tumors, tails of arrow represent correlation for non-responsive tumors. P-values were associated to the combination of correlation difference, as delineated in A. Colors represent different datasets. On the left, details of metagene are plotted, for ER-stress, lysosomes and autophagy (the name of a metagene is defined by its most representative gene).

Mentions: To respond to these questions, we followed a strategy (Figure 7A) that involved the generation of reproducible metagenes with the consequent exclusion of non-reproducible metagenes (as in Figure 1), the meta-analysis of correlations among metagenes and the subsequent exclusion of non-reproducible correlations (as in Figure 3), followed by the analysis of correlations among metagenes that differ between responders and non-responders, including only those differences that showed some degree of coherence among the four analyzable cohorts (with a combined p-value calculated according to Fisher's exact test of p < 0.05). Only very few correlations among immune cell type-related metagenes differed among responders and non-responders (Figure 7B). Thus the correlation between a metagene reflecting the intratumoral presence of Th2 cells and other leukocyte subtypes (T cells, neutrophils, macrophages, cytotoxic cells, B cells) tended to have higher R values in non-responders (start of the arrows in Figure 7B) than in responders (arrowheads in Figure 7B), although these trends were not uniform among all four cohorts.


Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies.

Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G - Oncotarget (2015)

Variability of metagene correlations, upon treatment response in breast cancerA. Flow chart for producing B & C. (B & C) Metagene correlations, when they are significantly different upon treatment response, B. for immune metagenes, C. for correlations between immune metagenes and ER-stress (C.1), lysosome (C.2), autophagy (C.3). Heads of arrow represent correlations for responsive tumors, tails of arrow represent correlation for non-responsive tumors. P-values were associated to the combination of correlation difference, as delineated in A. Colors represent different datasets. On the left, details of metagene are plotted, for ER-stress, lysosomes and autophagy (the name of a metagene is defined by its most representative gene).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494912&req=5

Figure 7: Variability of metagene correlations, upon treatment response in breast cancerA. Flow chart for producing B & C. (B & C) Metagene correlations, when they are significantly different upon treatment response, B. for immune metagenes, C. for correlations between immune metagenes and ER-stress (C.1), lysosome (C.2), autophagy (C.3). Heads of arrow represent correlations for responsive tumors, tails of arrow represent correlation for non-responsive tumors. P-values were associated to the combination of correlation difference, as delineated in A. Colors represent different datasets. On the left, details of metagene are plotted, for ER-stress, lysosomes and autophagy (the name of a metagene is defined by its most representative gene).
Mentions: To respond to these questions, we followed a strategy (Figure 7A) that involved the generation of reproducible metagenes with the consequent exclusion of non-reproducible metagenes (as in Figure 1), the meta-analysis of correlations among metagenes and the subsequent exclusion of non-reproducible correlations (as in Figure 3), followed by the analysis of correlations among metagenes that differ between responders and non-responders, including only those differences that showed some degree of coherence among the four analyzable cohorts (with a combined p-value calculated according to Fisher's exact test of p < 0.05). Only very few correlations among immune cell type-related metagenes differed among responders and non-responders (Figure 7B). Thus the correlation between a metagene reflecting the intratumoral presence of Th2 cells and other leukocyte subtypes (T cells, neutrophils, macrophages, cytotoxic cells, B cells) tended to have higher R values in non-responders (start of the arrows in Figure 7B) than in responders (arrowheads in Figure 7B), although these trends were not uniform among all four cohorts.

Bottom Line: Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts.Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies.Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.

No MeSH data available.


Related in: MedlinePlus