Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer

Abstract

BackgroundImmune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored.ResultsThe median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1–70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04).Materials and MethodsWe retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed.ConclusionsThere are significantly fewer TILs in brain metastases than in primary breast tumors.

Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer

“…Thus, it is reasonable to suggest that tumor-associate macrophages (TAMs) may also exert immunosuppressive roles in the immune microenvironment of brain metastases. Our immune gene expression profiling and pathways analyses are also in line with previous reports demonstrating reduced TILs in brain metastases compared with matched primary tumors of lung and breast cancer patients [21,22]. Accordingly, we also observed markedly suppressed expression of VCAM1, a molecule that plays crucial roles in mediating the adhesion of various leukocytes [16].…”

Alterations in Immune-Related Genes as Potential Marker of Prognosis in Breast Cancer

“…The brain is a natural immune exemption zone because of the blood-brain barrier, and thus, its microenvironment is very different from that in breast cancer. Compared with primary breast cancer, paired brain metastases presented significantly lower TIL abundance (45). The expression of the CAF-related proteins stromal podoplanin, stromal PDGFRα and stromal PDGFRβ is reduced in brain metastases (46).…”

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

“…Alternatively, resistance could be caused by the activation of other signaling pathways in the tumor cells by the brain microenvironment, such as the aforementioned PI3K‐AKT and CDK4 pathways (Chen et al, ; Niessner et al, ). An immunosuppressive microenvironment in the brain could also contribute, as previous studies support a role for the antitumor immune response in the activity of targeted therapies (Berghoff et al, ; Hamilton et al, ; Ogiya et al, ). Finally, metabolic changes in tumor cells, which have been observed in brain metastases in preclinical models, could also contribute to resistance (Ciminera et al, ; Gopal et al, ; Palmieri et al, ).…”

“…A number of other clinical trials, focusing upon the utility of checkpoint inhibitor therapies in patients with MBM, were discussed by Dr. Hussein Tawbi (MD Anderson Cancer Center, Houston, TX). Dr. Tawbi reviewed the evidence that MBM show decreased antitumor immune responses compared to extracranial tumors and that decreased immune infiltration may correlate with inferior outcomes in patients with brain metastases (Berghoff et al, ; Hamilton et al, ; Ogiya et al, ). It is known that large or rapidly growing MBM frequently cause cerebral edema and often require treatment with steroids to control symptoms, which may impact the immune response.…”