Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

Abstract

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

“…Conversely, many fewer significant changes were found in basal-like metastatic tumors relative to primary, with the major changes being decreases in the vast majority of immune signatures (B cells and T cells), signatures related to EMT, and stromal features, in agreement with previous studies (77)(78)(79)(80)(81). We did not observe any significant differences between primary and metastases in all proliferation-related scores or modules analyzed in basal-like paired tumors ( Figure 6E, Supplemental Table 9, and Supplemental Figure 10B), contrasting with the luminal set ( Figure 6, C and D).…”

Neural Network Deconvolution Method for Resolving Pathway-Level Progression of Tumor Clonal Expression Programs With Application to Breast Cancer Brain Metastases

“…We also observed recurrent gains in ErbB pathway, as indicated by the primary studies (Priedigkeit et al, 2017;Vareslija et al, 2018). Three pathways related to immune activity are underexpressed in metastatic samples, including Cytokine-cytokine receptor interaction (Lee and Margolin, 2011), JAK-STAT (Lee and Margolin, 2011), and Notch (Aster et al, 2017), consistent with the previous inference of reduced immune cell expression in metastases in general and brain metastasis most prominently (Zhu et al, 2019). We can suggest that this result similarly may reflect expression changes in infiltrating immune cells, due to the immunologically privileged environment of the brain, rather than expression changes in tumor cell populations.…”

Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma

“…Similar observations were made in other tumors like metastatic breast cancer that is characterized by lower immune cell infiltration relative to its paired primary tumor. 28 Several clinical studies on immune checkpoint inhibitors (ICIs), which flare up antitumor immune responses, showed major therapeutic improvements in many tumor entities. The first approved cytotoxic T-lymphocytes antigen-4 (CTLA-4) inhibitor, ipilimumab, demonstrated enormous success in advanced melanoma.…”