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. Author manuscript; available in PMC: 2022 Jan 31.
Published in final edited form as: Cancer Discov. 2020 May 5;10(9):1296–1311. doi: 10.1158/2159-8290.CD-19-1416

Figure 3. Loss of Fbxw7 is associated with altered immune microenvironment and decreased interferon signaling.

Figure 3.

(a) Heat map showing the expression of an immune-related gene signature associated with response to pembrolizumab in Fbxw7-deficient and control D4C9 tumors pre- or post-treatment with anti-PD-1. (b) Volcano plot showing relative expression of Nanostring immune transcripts in Fbxw7-deficient versus control D4C9 tumors after treatment with anti-PD-1. Highlighted in red are genes expressed in response to interferons or viral sensing. The p-value was generated as described in nCounter Analysis System User Manual. (c) Specific viral sensing and pro-inflammatory transcript ratios in Fbxw7-deficient (n=10) and control (n=3) D4C9 tumors after treatment with anti-PD-1. Unpaired t-test was used to determine statistical significance. *, P <0.05; **, P <0.01; ***, P <0.001; ****, P <0.0001. (d-e) Relative (d) Cxcl10 and (e) Ifnb1 mRNA expression in control and Fbxw7-deficient D4C9 tumors. Each dot represents a biological replicate. Unpaired t test was used to determine statistical significance. *, P <0.05. (f-h) Flow cytometry analysis of (f) CD8+ T cell, (g) dendritic cell and monocytes, and (h) macrophage infiltration in Fbxw7-deficient and control D4C9 tumors after treatment with control isotype or anti-PD-1. Each dot represents a biological replicate. One-way ANOVA with Sidak’s multiple comparisons test was used to determine statistical significance. *, P <0.05; **, P <0.01; ***, P <0.001. (i) Gene set enrichment analysis comparing gene expression of FBXW7-mutant and wild-type tumors. Highlighted in red are the decreases of the interferon response and inflammatory signatures in FBXW7-mutated cancer. NES: Normalized Enrichment Score. (j) Enrichment score plots for the indicated gene sets. Vertical bars refer to individual genes in a gene set and their position reflects the contribution of each gene to the ES. (k) Spearman correlation of FBXW7 mRNA levels with CD8A mRNA levels across TCGA cancers. Each dot represents a cancer type in TCGA, red dots indicate significant correlation with P < 0.05. SKCM, skin cutaneous melanoma; BRCA, breast carcinoma; PRAD, prostate adenocarcinoma; UCEC, uterine corpus endometrial carcinoma; READ, rectum adenocarcinoma. Additional data in Supplementary Table 5.