Researchers Identify Possible Source of Inflammatory Response Disparity in Black, White Women With Breast Cancer

A more aggressive tumor microenvironment (TME) may be to blame for the exaggerated inflammatory response more often seen in Black women with breast cancer compared with White women, according to findings from Roswell Park Comprehensive Cancer Center published last week in Journal of the National Cancer Institute.

These results take on even greater importance in light of the breast cancer mortality rate being 40% higher in Black vs White women, noted a press statement announcing the findings.

“We observed in the tumor microenvironment of breast cancer in patients of African descent a distinct signature of exhausted versus total CD8+ T cells, and noted further that this immune cell profile is associated with poorer breast cancer survival,” said first author Song Yao, PhD, professor of oncology, Department of Cancer Prevention and Control at Roswell Park, in the statement.

Following the investigators’ profiling of infiltrating immune cells taken from the breast tumors of 1315 patients from the Women’s Circle of Health Study (WCHS), Black women were shown to have a more exhausted CD8+ T-cell profile despite having a stronger CD4+/B-cell response. These results did not change with tumor subtype. They also build on previous findings “that tumor biology may play a role in these racial disparities,” the authors noted.

They used The Cancer Genomic Atlas (TCGA) to validate the racial differences first identified in the immune infiltrates of the WCHS participants and TCGA plus the Molecular Taxonomy of Breast Cancer International Consortium to analyze tumor immune phenotype survival.

Pathologic tumor infiltrating lymphocyte (TIL) scores were higher overall among the Black women, even when accounting for race and hormone receptor subtype (P ≤ .0001). Similar associations were not found when human epidermal growth factor receptor 2 status was considered.

Altogether, the increased rates of all-cause and disease-specific mortality seen among the Black women were consistently associated with their higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r), especially those with hormone receptor–positive disease. For women with hormone receptor–negative disease, however, only those in the CD8-low/ExCD8-r–high subgroup had worse outcomes.

In comparison, a lower all-cause mortality (HR, 0.38; 95% CI, 0.19-0.76) was seen among the patients with lymphocyte-predominant breast cancer (TIL score ≥ 50%) vs lymphocyte-depleted breast cancer (TIL score < 10%).

According to the authors, the biggest racial differences in immune infiltrates were seen with the lower fractions of neutrophils and dendritic cells but higher fractions of CD4+ T cells in the Black study participants, as well as a statistically significant difference in T follicular helper cells.

“We found statistically significant and consistent racial differences in immune infiltrates in the breast TME, in particular, a CD8+ T-cell response shifted towards an exhausted state in Black patients,” the authors concluded. “These findings may explain the contradiction of a strong immune presence in the breast TME of Black patients, yet poorer survival, providing a new immunobiological perspective to underlying causes of breast cancer racial disparities.”

They believe their findings indicate that Black patients may have a higher response rate to checkpoint inhibitor therapy, which is supported by their stronger B-cell response.

To close the racial disparity in cancer outcomes, the authors highlighted the importance of identifying germline genetic variants and their relationships to tumor immunophenotypes among patients of different races, as well as stepping up minority recruitment for clinical trials.

Reference

Yao S, Cheng T-Y D, Elkhanany A, et al. Breast tumor microenvironment in black women: a distinct signature of CD8+ t-cell exhaustion. J Natl Cancer Inst. Published online January 5, 2021. doi:10.1093/jnci/djaa215