Abstract
Tumor-infiltrating lymphocyte (TIL) levels have prognostic and predictive values in treatment-naïve breast cancers. However, there have been controversies regarding TIL subset changes and their clinical implications in post-treatment breast cancers. This study aimed to explore change and prognostic significance of TIL subset infiltration after primary systemic therapy (PST) in breast cancer. One-hundred-fifty-five patients who had residual disease after anthracycline- or anthracycline plus taxane-based PST were included. The quantities of intratumoral and stromal TIL subsets (CD8+, CD4+, and FOXP3+ TILs) in pre- and post-PST breast cancer samples, as well as changes between them, were analyzed along with their correlations with clinicopathologic features and outcome of patients. As a whole, intratumoral CD8+ and CD4+ TILs increased after PST while stromal TILs decreased. Both intratumoral and stromal FOXP3+ TILs decreased after PST. The chemo-sensitive group [residual cancer burden (RCB) class I and II] showed the same pattern of change in intratumoral CD8+ TILs as the whole group, whereas the chemo-resistant group (RCB class III) showed no significant change in intratumoral CD8+ TIL infiltration after PST. Survival analyses for each TIL subset as well as their ratios revealed that high levels of intratumoral, stromal, and total CD8+ TIL infiltration after PST were independent predictors of longer patient survival. In subgroup analyses, CD8+ TIL infiltration after PST revealed prognostic significance in the chemo-resistant group but not in the chemo-sensitive group. In conclusion, infiltration of CD8+, CD4+, and FOXP3+ TIL changed after PST in the intratumoral and stromal compartments. Especially, increase of intratumoral CD8+ TILs was associated with chemo-responsiveness. Moreover, CD8+ TIL status in residual tumors after PST may be used as a potential prognostic marker in breast cancer patients who receive PST and provide additional prognostic information to chemo-resistant group.
Highlights
Studies of the dynamic interaction between tumor cells and the immune system have established a new era in cancer research and treatment
Tumor-infiltrating lymphocyte (TIL) are of predictive and prognostic values in breast cancer patients treated with Primary systemic therapy (PST); the presence of high TILs in pretreatment biopsy samples is a significant predictor of the response to PST [12, 13] and the presence of high TILs in residual disease is an indicator of better prognosis, especially in triple-negative breast cancer (TNBC) patients [14,15,16]
We explored changes in TIL subsets including CD8+, CD4+, and FOXP3+ T cells after PST, and found that total CD8+ and CD4+ TIL infiltration did not show significant change after PST, while FOXP3+ TILs decreased
Summary
Studies of the dynamic interaction between tumor cells and the immune system have established a new era in cancer research and treatment. High levels of tumor-infiltrating lymphocytes (TILs) generally indicate a more robust anti-tumor immune response, and have been shown to be associated with favorable clinical outcomes in patients with breast cancer, especially in those with triple-negative breast cancer [1,2,3]. Among TIL subsets, cytotoxic CD8+ T cell infiltration is considered a key indicator of effective antitumor immunity, and high CD8 + TILs have been associated with favorable clinical outcome [4, 5]. FOXP3+ regulatory T cells, which are known as CD4+CD25+ Tregs, have suppressive effects on the anti-tumor immunity, and have been associated with poor clinical outcome [8,9,10]. Higher levels of CD4+ and FOXP3+ TILs have been reported to predict pCR [17,18,19]
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