Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8 ⁺ T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer ( n = 131). Among tissue-resident memory CD8 ⁺ T (T _RM ) cells, including virus- and tumor-specific CD8 ⁺ T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39 ⁺ T _RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39 ⁺ T _RM cells clonally overlapped with CD39 ⁻ T _RM and non-T _RM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39 ⁺ T _RM clonotypes were frequently detected among effector memory CD8 ⁺ T cells in peripheral blood, suggesting a systemic clonal overlap. CD39 ⁺ T _RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39 ⁺ T _RM cells and enhanced cytokine production by CD8 ⁺ T cells from tumors or mLNs, particularly in the presence of CD39 ⁺ T _RM enrichment. This suggests that CD39 ⁺ T _RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39 ⁺ T _RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.

Radiotherapy (RT) is the standard of care following breast-conserving operation in breast cancer patients. The neutrophil-to-lymphocyte ratio (NLR) reflects the systemic change caused as a result of the radiotherapy. We aimed to evaluate the association between RT and the change in NLR following the receipt of RT, and to investigate the prognostic impact. We retrospectively reviewed NLR values of breast cancer patients taken before the administration of the first and the last session of RT. The cut-off point for the NLR was determined using the Youden index and receiver operating characteristic (ROC) curve within the training set. Recurrence-free survival (RFS), distant metastasis free survival, and overall survival were the main outcomes. Patients with an NLR higher than 3.49 after RT were classified to an RT-induced high NLR group and showed a significantly higher recurrence rate compared to those with low NLR (p < 0.001). In a multivariate Cox proportional hazards model, RT-induced high NLR remained a significant prognostic factor (HR 2.194, 95% CI 1.230–3.912, p = 0.008 for tumor recurrence. We demonstrated that an increase in NLR over the course of RT has a negative impact on survival, putting these patients with RT-susceptible host immunity at a higher risk of tumor recurrence.

Bae SJ, et al. J Breast Cancer. 2018 Jun;21(2):190-196. https://doi.org/10.4048/jbc.2018.21.2.190

Recent studies have shown that tumors with extensive tumor-infiltrating lymphocytes (TILs) have a higher probability of pathologic complete response, even in luminal/human epidermal growth factor 2 (HER2)-negative breast cancer. We compared TIL levels and the 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer. We evaluated the percentage of stromal TILs in 198 ER-positive/HER2-negative patients in whom RS was obtained by examining slides of surgical specimens by standardized methodology proposed by the international TIL Working Group. TIL levels were categorized as high (≥ 60%), intermediate (11–59%), or low (≤ 10%). All tumors were treatment-naïve. Ninety-seven (49.0%), 88 (44.4%), and 13 patients (6.6%) had low, intermediate, and high TIL levels, respectively. There was a significant but weak correlation between continuous RS and continuous TIL levels (Pearson’s R = 0.201, p = 0.004). The mean RS was significantly highest in high TIL tumors (17.8 ± 10.7 in low TIL tumors, 19.4 ± 8.7 in intermediate TIL tumors, and 26.2 ± 8.2 in high TIL tumors; p = 0.014). However, when we compared categorized RS and TIL levels, we found that tumors with high TIL levels tended to have higher RS (≥ 26) but it was not significant (p = 0.155). Furthermore, multivariate analysis revealed that high RS was not an independent factor associated with high TIL levels. Chemo-endocrine therapy was more frequently performed among patients with high TILs and less frequently among those with low or intermediate TILs (p < 0.001). Despite of a weak correlation between continuous TIL levels and RS, we found that tumors with high TIL levels tended to have a higher RS in ER-positive/HER2-negative breast cancer. Further study is warranted considering the clinical outcomes.

Baek SH, et al. J Breast Cancer. 2018 Dec;22:e7. https://doi.org/10.4048/jbc.2019.22.e7