Breast Tumor Microenvironment in Black Women

A Distinct Signature of CD8+ T-Cell Exhaustion

Song Yao, PhD; Ting-Yuan David Cheng, PhD; Ahmed Elkhanany, MD; Li Yan, PhD; Angela Omilian, PhD; Scott I. Abrams, PhD; Sharon Evans, PhD; Chi-Chen Hong, PhD; Qianya Qi, MS; Warren Davis, PhD; Song Liu, PhD; Elisa V. Bandera, MD, PhD; Kunle Odunsi, MD, PhD; Kazuaki Takabe, MD; Thaer Khoury, MD; Christine B. Ambrosone, PhD

Disclosures

J Natl Cancer Inst. 2021;113(8):1036-1043. 

In This Article

Discussion

Our findings of stronger overall immune response in breast tumors from Black women compared with White women are consistent with results from a prior TCGA analysis showing that African ancestry was associated with a higher leukocyte fraction in breast tumors,[21] as well as those from a study in colorectal cancer, showing a stronger lymphocytic reaction in Black patients.[33] As Black individuals tend to exhibit stronger inflammation-related systemic immunity,[8–10] these data together suggest that it may give rise to stronger immune responses in the TME among Black women with breast cancer.

Our data support the notion that the composition and quality of immune infiltrates may be as important as their absolute presence in the TME. Black patients have tumor immune reactions shifted toward humoral immunity characterized by higher levels of CD4+ T cells, TFH cells, B cells, and BCR clonality. Although the antineoplastic activity of humoral immunity has been less well understood than cellular immunity, several recent studies have demonstrated the importance of TFH cells and B cells in immunotherapy.[34–37] Moreover, Black patients also exhibited a T-cell response of exhaustion features associated with poor survival, possibly because of diminished effector cytokine production and cytolytic activity.[26] Thus, it may be the higher proportion of the T-cell exhaustion feature among Black patients that accounts for the seeming contradiction of poorer survival outcomes, despite the stronger overall immune presence of TILs in the TME.

The greater presence of exhausted immune phenotypes in tumors from Black women is consistent with the premise that a more active and prolonged inflammatory immune response in individuals of African descent, shaped over millennia in tropical Africa, could be related to more aggressive breast cancer.[7,38] Host immunity is among the biologic mechanisms most frequently subject to natural selection[39,40] driven by infectious pathogens, a major environmental force in recent human evolutionary history.[41] Because tropical regions in Africa are rich in pathogenic agents, early populations likely benefited from a more active immune defense, and genetic variants that enhance immune responses were likely positively selected. Indeed, allele frequencies of immune genes often display large, and sometimes extreme, racial differences.[42,43] A potential approach to further investigate this hypothesis is to identify germline genetic variants in association with tumor immunophenotypes in racially diverse populations, ideally through genome-wide methods. Probably more than a coincidence, the only genome-wide significant association identified in a recent study of tumor immunophenotypes was between a variant in SIK and TFH cells,[24] which happened to be the most statistically significantly differentially occurring CD4+ T-cell subset found in our study, and the variant has a much higher allele frequency in Blacks than in Whites. Given the limited sample size of our study, a genome-wide study of genetic variations is out of scope, but future studies in this area are warranted.

The literature indicates that hormone receptor–negative breast cancers are more immunologically "hot" than hormone receptor–positive tumors,[44,45] and our data support that premise. Interestingly, the ExCD8-r signature was prognostic only among hormone receptor–positive but not hormone receptor–negative cancers. A new study using single cell proteomics also revealed CD8+ T-cell exhaustion in a subset of hormone receptor–positive breast cancers characterized by increased PD-1 and IR co-expression.[46] In another study of patients with estrogen receptor–positive cancer, expression feature of CD8+ PD-1+/CTLA-4+ predicted response to immunotherapy.[47] These data suggest that even among the immunologically "cold" hormone receptor–positive breast cancers, tumor immune response is relevant to patient survival and could potentially be targeted for immunotherapy, which is currently being evaluated in clinical trials. The finding may also have relevance to breast cancer health disparities, because some studies reported that the most persistent Black–White differences in breast cancer survival occurred within hormone receptor–positive cancers.[48]

Our findings of distinct tumor immune responses in Black breast cancer patients may have clinical implications. Immune checkpoint inhibitors target the inhibitory receptors expressed on T cells, and their corresponding ligands on tumor or stromal populations such as myeloid cells, to reinvigorate the exhausted effector CD8+ T cells. The apparently stronger but more exhausted lymphocytic state in Black patients implies that a higher response rate to checkpoint inhibitors might be expected. Further, the stronger B-cell response in Black patients and the newly discovered role of tumor-infiltrating B cells in regulating response to immunotherapy provide further support this postulation. To our knowledge, however, few clinical trials on immune checkpoint inhibitors have reported race-specific outcome data. Enhanced recruitment of racial and ethnic minorities into clinical trials is warranted to close the gaps in cancer disparities and to ensure that all groups of patients will benefit from advances in cancer therapeutics.[49]

In summary, we found statistically significant and consistent racial differences in immune infiltrates in the breast TME, in particular, a CD8+ T-cell response shifted toward an exhausted state in Black patients. 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.

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