Abstract
The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the three major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER+, 207 HER2+, and 191 triple-negative (TNBC) cancers from The Cancer Genome Atlas. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers. Cancer Res; 77(12); 3317-24. ©2017 AACR.
Highlights
The presence of immune infiltration in the breast cancer microenvironment is a favorable prognostic marker among triple-negative (TNBC), HER2þ and highly proliferative estrogen receptor (ER) positive cancers [1]
The lymphocyte-specific kinase (LCK) metagene showed high average correlation with other immune metagenes across all subtypes and this metagene has showed a strong correlation with histologic tumor-infiltrating lymphocytes (TIL) counts in breast cancer samples in a previous study [5], which we have observed in our data (Supplementary Fig. S2), we selected this metagene as the best single measure of immune infiltration
When compared across breast cancer subtypes, the LCK metagene expression, mutation count, neoantigen load and amplification, and deletion loads were all higher in TNBC compared to the other breast cancer subtypes
Summary
The presence of immune infiltration in the breast cancer microenvironment is a favorable prognostic marker among triple-negative (TNBC), HER2þ and highly proliferative estrogen receptor (ER) positive cancers [1]. High levels of immune infiltration, measured as either TIL count or expression of immunecell related genes, predicts for better survival with or without systemic adjuvant therapy in early stage disease [2,3,4,5,6]. Breast cancers that are rich in immune cells, regardless of subtype, have higher rates of pathologic complete response (pCR) to neoadjuvant chemotherapy [7, 8]. The extent of immune infiltration is higher in TNBC and HER2þ cancers than in ERþ disease [7]. The biological mechanisms underlying the variable TIL infiltration are unknown
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