Basal-Like Breast Cancer Is Associated with Both an Enhanced Cytotoxic and Regulatory T-Cell Response
Elizabeth Kalife, Shaolei Lu, Shamlal Mangray, Rose Tavares, Lelia Noble, Murray Resnick, Evgeny Yakirevich. Warren Alpert Medical School of Brown University, Providence, RI
Background: Tumor infiltrating lymphocytes (TILs), the primary immune component infiltrating solid tumors, are considered a manifestation of the host antitumor reaction. The majority of TILs are CD3+ T-cells which include CD8+ cytotoxic T-lymphocytes (CTLs) and FoxP3+ regulatory T-cells (Tregs). These subsets have a unique role in promotion or suppression of the immune response and have proven prognostically significant in some tumors. Our goal was to investigate the type, distribution and density of TILs in different molecular subtypes of breast carcinoma.
Design: Tissue microarrays were constructed from 189 consecutive cases of high grade invasive ductal carcinoma. On the basis of IHC expression, the tumors were stratified into 54 luminal (ER+), 59 HER2 positive (HER2+) and 76 basal-like (ER-, HER2-, CK5/6 and/or EGFR+). TILs were assessed by IHC for CD3, CD8, granzyme B (activated CTLs) and FoxP3. The TIL subsets were quantitated separately in intratumoral and stromal compartments. The mean number of positively stained TILs was normalized per 0.785 mm2 of tumor.
Results: The number of intratumoral CD3+ TILs was higher, albeit not significantly, in the basal-like type, as opposed to luminal and HER2 types (44.9±6.3, 37.1±13.9, 40.1±11.8). Significantly higher numbers of intratumoral CD8+ CTLs were found in the basal-like type compared to luminal and HER2 types (26.7±4.0, 11.6 ±1.9, 19.6±4.0; p=0.02). Granzyme B+ activated CTLs were also significantly increased in the basal-like type compared to the luminal and HER2 types (18.0±3.8, 3.3±1.2, 10.8±3.7; p=0.018). Paradoxically, basal-like tumors contained significantly higher numbers of FoxP3+ Tregs than the luminal and HER2 types (15.4±2.5, 6.1±1.35, 8.9±1.7; p=0.02). Using the median number as cutoff, we found that the basal-like type was associated with significantly higher recruitment of both granzyme B+ high and FoxP3+ high TILs than the luminal type (60% vs 7.4%; p=0.0001). No significant differences were found among the number of stromal TILs in the different tumor subtypes. Survival analysis revealed that tumor stage was predictive of overall survival (p<0.0001). The TIL distribution was not associated with patient survival.
Conclusions: The distribution of activated granzyme B+ CTLs and FoxP3+ Tregs differs among the molecular subtypes of breast cancer. The basal-like type is characterized by a unique immune response comprised of both increased cytotoxic and regulatory TILs. This may be one of the reasons that despite having increased numbers of CTLs, the basal-like type confers a poorer prognosis.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 24, Monday Morning