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. 2014 Jan 1;3(1):e27884.
doi: 10.4161/onci.27884. Epub 2014 Feb 27.

Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy

Gautier Stoll  1 , David Enot  2 , Bernhard Mlecnik  3 , Jérôme Galon  3 , Laurence Zitvogel  4 , Guido Kroemer  5
Affiliations

Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy

Gautier Stoll et al. Oncoimmunology. .

Abstract

There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients. No consistent correlations between immune- and stress-related metagenes could be identified across several cohorts of patients, representing a total of 1045 mammary carcinomas. Moreover, few if any, of the stress-relevant metagenes influenced the probability of pathological complete response to chemotherapy. In contrast, several immune-relevant metagenes had a significant positive impact on response rates. This applies in particular to a CXCL13-centered, highly reproducible metagene signature reflecting the intratumoral presence of interferon-γ-producing T cells.

Keywords: autophagy; breast cancer; colorectal cancer; endoplasmic stress; immunogenic cell death; tumor-infiltrating lymphocytes.

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Figures

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Figure 1.P value of metagene reproducibility. Each of the candidate metagenes per category constructed from The Cancer Genome Atlas (TCGA) cohort (listed in Table S1 and named according to the highest weighted gene in the signature) was revaluated in other cohorts, as indicated, and P values were determined by bootstrapping. Metagenes are ranked left to right according to their reproducibility. Box plots of the P values are shown for each group of metagenes per category. Plain and dashed yellow lines delimit highly- (P value < 0.05 for all cohorts), median- (P value < 0.05 for all cohorts except 1) and non-reproducible metagenes.
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Figure 2. Salient features of reproducible metagenes. Listed are the most important genes contributing to metagenes defined as highly or median-reproducible in Figure 1. The relative weight of the listed individual mRNA species within each metagene is gray-coded and reflect the correlation coefficient (“component” column of metagene-associated genes listed in Tables S1–4). Shown are only those genes whose coefficient is above 0.14. Genes related to the tumor-associated immune microenvironment are highlighted: red = cytokines, blue = natural killer, green = human leukocyte antigen.
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Figure 3. Pearson’s correlations between metagenes within each of the 4 functional categories as determined in 4 distinct breast cancer cohorts. A–D. Reproducibility (P value) calculated based on the variance between metagene data sets within the indicated cohort. E–F. Box plots of correlation matrix (E) elements (or r-values) calculated relative to the TCGA cohort and reproducibility P values (F), either for the complete set of metagenes (in white) or focusing on the subset of reproducible metagenes (in yellow) delimited by yellow lines in A–D (as described in Fig. 1 legend). Zero (black) indicates that the pair are uncorrelated, a positive value (red) indicating a correlation and a negative value (green) indicating an inverse relationship.
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Figure 4. Pearson correlations (or r-values) between immune-relevant and stress response-relevant metagenes. A–C. Reproducibility (P value) was calculated based on the variance between data sets and by comparison with a null hypothesis distribution (2000 events). D–E. Box plots (D) of correlation matrix elements (or r-values) calculated relative to the TCGA cohort and reproducibility P values (E) either for the complete set of metagenes (in white) or focusing on reproducible metagenes (in yellow) delimited by yellow lines in A–C.
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Figure 5. Metagenes derived from target genes of stress-responsive transcription factors. A–G. Analysis of metagenes (see Table S5) derived from the downstream targets of ATF4 (A), ATF6 (B), XBP1 (C) and TFEB (D) transcription factors. A–D. Upper panels indicate the P value of metagene reproducibility in 6 distinct cancer cohorts (refer to Fig. 1 legend for details). Middle panels display Pearson’s correlations (or r-values) between immune-relevant metagenes and each of the new metagenes within the TCGA cohort. Yellow lines delimit different levels of reproducibility as described in Figure 1. Lower panels summarize the reproducibility among additional breast cancer cohorts (similar to Fig. 4). E–G. Box plots of p-value reproducibility (E; derived from the upper panels in A–D), correlation matrix elements (or r-values) calculated relative to the TCGA cohort (F; derived from the middle panels in A–D) and correlation reproducibility (G; derived from the gray-shaded graphs in the lower panels in A–D).
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Figure 6.A–H. Heat map of significance of differential metagene expression between chemotherapy responding and non-responding patients. Signed log P values were computed for each immune (A), ER-stress (B), autophagy (C) or lysosomal (D) response-relevant metagenes (yellow lines delimit different levels of reproducibility as determined in Figure 1,or transcription factor-determined (E–H) metagenes by one-tailed, unpaired Student’s t tests to compare the transcript levels in tumors that underwent complete pathological responses (cPR) with those that failed to respond to chemotherapy. This calculation was done for each cohort and treatment option separately. The “combined” rows represent the signed log P value obtained by the aggregation of the individual data set values by means of Fisher’s method. The color scale represents log (base 10) of P values, with a positive or negative sign to indicate over (red) or under (green) expression, respectively, in samples from patients with cPR relative to samples from non-responders.
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