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Brain Metastases Analysis Points to Distinct Tumor Immune Microenvironments, Potential Treatments

NEW YORK — Researchers have characterized the tumor immune microenvironments of brain metastases from individuals with primary lung or breast cancer, identifying immunophenotypes that could inform treatment choices or aid in the development of new therapies.

Brain metastases are the most common form of brain cancer affecting adults and typically originate from lung or breast primary tumors. They are associated with high mortality, as only a small portion of patients with brain metastases respond to current treatments.

Since some studies have suggested treatment response may be influenced by the tumor immune microenvironment (TIME), a Swiss team of researchers set out to characterize the TIMEs of samples from 30 individuals with brain metastases (BrMs). Through their immunogenetic profiling, the researchers uncovered specific immunophenotypes associated with genetic alterations in lung and breast cancers, including some that show higher immune cell infiltration and others that are more immunosuppressive.

"[This study offers] evidence for an association between specific genetic alterations and unique TIME immunophenotypes in human BrMs," senior author Johanna Joyce, a cancer biologist at the University of Lausanne in Switzerland, and her colleagues wrote in their paper. "This knowledge can be of critical importance to predict responses to current immunotherapies, to stratify patients, and to develop novel immune-based personalized treatments guided by the genetic makeup of the tumors."

For their study, which appeared Tuesday in Cell Reports Medicine, the researchers analyzed surgically resected brain metastasis tissue and matched peripheral blood from 30 patients, 21 with primary lung cancer and nine with primary breast cancer. For each, they conducted whole-exome or low-pass whole-genome sequencing, flow cytometry and RNA sequencing of sorted immune cell populations, and immunofluorescence tissue analysis.

The lung-origin brain metastases had slightly higher average mutational load than lung primary tumors in The Cancer Genome Atlas, they found, noting that this is in line with models of metastases. Within this sample set, the most commonly mutated cancer driver genes were TP53 and KRAS, consistent with previous reports.

Based on that, they divided their lung-origin brain metastasis cohort into four genetically distinct groups — metastases with TP53 mutations; with TP53 and KRAS mutations; with KRAS mutations; and with neither — and examined the different characteristics of each group. Brain metastases with TP53 mutations and those with both TP53 and KRAS mutations, for instance, harbored more mutations than the other two groups and displayed more neoantigens.

At the same time, the researchers conducted an analysis of breast-origin brain metastases, which similarly identified TP53 mutations as the most common cancer driver in that sample set. Like the lung-origin brain metastases, these breast-origin brain metastases also had higher average mutational loads compared to primary breast tumors.

Further, mutational signatures among these breast-origin brain metastases pointed to activity of the APOBEC/AID family of deaminases in the TIMEs. The APOBEC family, they noted, has been implicated in kataegis, or clusters of hypermutation in small genomic regions, which they identified within four of their samples.

These groups of lung- and breast-origin brain metastases with different genetic profiles further exhibited varying immune cell landscapes, which could point to potential treatment approaches, the researchers noted.

TP53-mutated lung-origin brain metastases, they found, had a distinctive immunophenotype characterized by a high mutational burden, increased T-cell infiltration, and immunosuppressive myeloid cells alongside upregulation of IL1R1 and IL1R2 in microglia and downregulation of TREM2 in microglia and monocyte-derived macrophages. This suggests that TP53-mutated lung-origin brain metastases might be more likely to respond to immunotherapies, the researchers said.

Kataegic breast-origin brain metastases, meanwhile, expressed high levels of a cytokine that recruits effector T cells and had higher levels of CD103+CD8+ T cells, indicating a more inflamed TIME. Patients with these metastases might benefit from immune checkpoint blockade or PARP inhibition therapies, they suggested.

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