Immune signature of metastatic breast cancer: Identifying predictive markers of immunotherapy response

Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park, Ji-Yeon Kim, Eunjin Lee, Kyunghee Park, Woong-Yang Park, Hae Hyun Jung, Jin Seok Ahn, Young-Hyuck Im, Yeon Hee Park

Abstract

In breast cancer (BC), up to 10-20% patients were known to have clinical benefit with immune checkpoint inhibitors, and biomarkers are needed for optimal use of this multi-potential therapeutic strategy. Accordingly, we conducted an experiment to identify expression of genes associated with immune checkpoints that represent potential targets of cancer immunotherapy. We performed whole-transcriptome sequencing and whole-exome sequencing using 37 refractory BC specimens. In the immune pathway gene set expression analysis, we found that HER2 expression and previous taxane treatment were positively correlated with high expression of immune gene set expression (p = 0.070 and 0.008, respectively). The nine genes associated with immune checkpoints - PDCD1(PD-1), CD274(PD-L1), CD276(B7-H3), CTLA-4, IDO1, LAG3, VTCN1, HAVCR2, and TNFRSF4(OX40) - interacted with each other. In addition, HER2 expression also affected the expression levels of these genes (p = 0.044). Lastly, expression of immune checkpoint genes and tissue-infiltrating lymphocytes were positively correlated in metastatic BCs (p < 0.001). In conclusion, we suggest that HER2 expression and previous taxane treatment are potential surrogate markers for high expression of immune checkpoint genes and immune pathway gene sets. Further study of the BC immune signature with large-scale, translational data sets is warranted.

Keywords: HER2 expression; breast cancer; immune checkpoint; immune signature; taxane.

Conflict of interest statement

CONFLICTS OF INTEREST

None.

Figures

Figure 1
Figure 1
(A) Ninety-one immune pathway gene set enrichment analysis (GSEA) in 37 metastatic BCs : the information of 91 genesets were described in supplementary Data; (B) The level of immune pathway gene set expression according to HER2 expression (p = 0.070); According to data of GSEA of 91 immune pathway gene sets, metastatic BCs were divided into 3 groups (highly activated, mixed and inactivated immune gene sets) And then the association between the level of immune pathway gene set activation and HER2 expression were analyzed. (C) The level of immune pathway gene set expression according to previous taxane chemotherapy (p = 0.008).
Figure 2
Figure 2
(A) Nine immune checkpoint gene (CD276, CD274, VTCN1, IDO1, HAVCR2, LAG, CTLA4, TNFRSF4 and PDCD1) expression profile in 37 metastatic BC; 10 breast cancer had high expression of nine immune check point genes and 27 did not. (B) Overall survival according to the level of immune checkpoint gene expression;(C) The level of immune checkpoint gene expression according to HER2 expression(p = 0.044); (D) The level of immune checkpoint gene expression according to previous taxane chemotherapy (p = 0.105).
Figure 3
Figure 3
(A) Tumor infiltrating lymphocyte markers expression in 37 metastatic BC; (B) Overall survival according to the level of tumor infiltrating lymphocyte markers.
Figure 4. Mutation burden in metastatic BCs
Figure 4. Mutation burden in metastatic BCs

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