Abstract
BackgroundEffector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively. However, it is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival.MethodsThe interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients.ResultsAmong the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20–0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19–0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135).ConclusionsBRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.
Highlights
Effector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer
The BRCA1 expression was negatively correlated with the T cell activation score
Given that the abundance and compositions of tumor infiltrating lymphocytes (TILs) are important in cancer immunotherapy, it warrants to further investigate how the TIL abundance and composition affect T cell activation and what factor(s) influences its abundance and composition. This is the first study to demonstrate the association of the BRCA1 expression level and the T cell activation score, and their interaction in patient survival in breast cancer
Summary
Effector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively It is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival. One is that other inhibitory molecules beyond CTLA4 and PD-1, for example, TIM3, LAG3 and TIGIT, are directly or indirectly, but synergistically involved in the exhaustion of effector T cells [12, 13] Another possibility is the insufficient amount of neoantigens on tumor cells. Several case reports show that patients who have better response to immune checkpoint blockade carry higher levels of MHC class I molecule in microsatellite unstable tumors [17,18,19] These findings warrant further studies to investigate how neoantigen loads in tumors affect patients’ response to immunotherapies
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