Reuters Health – 12/01/2021 – Black women with breast cancer exhibit an “exhausted” T-cell profile associated with poor survival, and may benefit from checkpoint inhibitor therapy targeting their unique phenotype, researchers suggest.
“Until now, triple negative breast cancer has been the only breast cancer subtype commonly treated with immunotherapy,” principal author Christine Ambrosone of Roswell Park Comprehensive Cancer Center in Buffalo, New York told Reuters Health by email. “Our findings that tumors from Black women have higher levels of exhausted immune cells indicate that, regardless of breast cancer subtype, immunotherapy may be effective in treating Black women with breast cancer.”
First author Dr. Song Yao, also of Roswell Park, added, “We have not studied directly what might be responsible for the exhausted immune phenotype, but one theory suggests that chronic inflammation and a robust immune response could contribute to this phenomenon. Because the origins of the human race were in tropical sub-Saharan Africa, rich in pathogenic agents, early hominid populations likely benefited from a more exuberant immune defense, with selection during evolution of genetic variants that enhance immune response.”
“As a result,” he said, “immune systems of patients with African ancestry may be more responsive and pro-inflammatory, leading to the development of exhausted immune phenotype and more aggressive cancers.”
As reported in the Journal of the National Cancer Institute, the authors characterized infiltrating immune cells in the breast tumor microenvironment (TME) of 1,315 participants in the Women’s Circle of Health (WCHS) Study.
They also used The Cancer Genomic Atlas (TCGA) breast cancer subset – comprised of 1,080 patients, including 180 Blacks and 714 Whites – and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; 1,904 Whites only). TCGA was used as a validation cohort for racial differences in immune infiltrates identified in WCHS; TCGA and METABRIC were used for a survival analysis of tumor immune phenotypes.
In addition, prognostic associations of immune phenotypes were assessed in three independent cohorts.
Marked and consistent differences in tumor immune responses were seen between Black and White patients. Tumors from Blacks displayed a stronger overall immune presence, but the composition and quality of immune infiltrates differed from those of Whites, regardless of tumor subtypes.
Black patients had a stronger CD4+/B cell response, and as noted earlier, a more exhausted CD8+ T cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor (HR)-positive patients.
Further, among HR-negative patients, combinations of the absolute fraction of CD8+ T cells and the ExCD8-r signature identified the CD8 (low)ExCD8-r (high)subgroup – the most prevalent among Blacks – with the worst survival.
The authors state, “It may be the higher proportion of T-cell exhaustion feature among Black patients that accounts for the seeming contradiction of poorer survival outcomes, despite the stronger overall immune presence of (tumor-infiltrating lymphocytes) in the TME.
Dr. Ambrosone said, “While we don’t yet have direct evidence to support preferential use of immunotherapy in Black breast cancer patients, it should be considered as a treatment option as viable as for White patients, especially considering the racial inequities in cancer treatment. Closer monitoring of immune-related toxicities in Black patients may also be warranted.”
Dr. Sandip Patel, Co-Leader, Experimental Therapeutics at the University of San Diego and Deputy Director, San Diego Center for Precision Immunotherapy, called the study “very important.” He told Reuters Health by email, “Anti-PD(L)1 immunotherapy is currently only active and FDA- approved in triple-negative breast cancer (a subset of HR-negative cancers) and some of the findings here confirm the biological basis for this clinical observation. Limited data exist on race-based differentials in immune response and further study is warranted.”
“Currently, we would favor all patients with triple-negative breast cancer receive anti-PD(L)-1-directed therapy (with a taxane) as part of their treatment in the metastatic setting,” he said. “If these findings are confirmed in larger studies or in clinical trials, understanding the unique immune basis of the unique T cell response in Black patients may help develop more personalized biomarkers for immunotherapeutic response or help drug discovery.”
The study “is a reminder for us to understand both biological as well as social determinants of health,” Dr. Patel concluded.
SOURCE: https://bit.ly/3oE7CIP Journal of the National Cancer Institute, online January 5, 2021.
By Marilynn Larkin
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