Abstract

Background

Immunosenescence, the age-related decrease in immune competence, is characterized by decreased adaptive immunity and increased low-grade inflammation. This may lead to altered anti-tumor immune responses and thus affect tumor immune infiltrate in older patients with cancer. However, detailed tumor infiltrate characterization in breast cancer (BC) has not yet been performed in the context of aging.

Methods

This exploratory study investigated age-related changes in the tumor microenvironment of patients with early BC (grade I-III, ER+, HER2-). Patients were subdivided into three age categories: 35-45 years (y) (N = 15), 55-65y (N = 19), ≥70y (N = 31). Stromal tumor infiltrating lymphocytes (sTILs) percentage was assessed following published guidelines. Immune infiltrate characterization was established by determining CD68 grade and scoring additional immune markers (CD3, CD4, CD5, CD8, CD20 and FOXP3) with a newly developed analysis pipeline using the QuPath software. In the oldest group, the geriatric 8 (G8) score was obtained as a correlate for clinical frailty level.

Results

With increasing age, sTILs percentage significantly decreased, concomitant with significantly lower Tcells (CD3⁺ and CD5⁺), cytotoxic Tcells (CD8⁺) and Bcells (CD20⁺) densities in the whole tumor area. When assessing tumor regions separately, significant age-related decreases in immune cell density in invasive front (CD3⁺, CD5⁺, CD8⁺, CD20⁺ cells) and tumor center (CD3⁺, CD5⁺, CD8⁺ cells) were observed. No age-related changes were seen for CD4⁺ and FOXP3⁺ cell infiltration nor for CD68 grade in the tumor. G8 score showed a significant inverse correlation with regulatory Tcells (FOXP3⁺) density in tumor center. However, spatial distribution of the immune cell populations did not depend on age nor frailty level.

Conclusion

In conclusion, sTILs percentage and density of several immune markers in the tumor significantly differed between young and older patients with BC. Moreover, density of regulatory T-cells was higher in frailer patients (lower G8 score). This may indicate that tumor immune responses in these patients may be less effective, and approaches for immunotherapy may vary depending on patients’ age/frailty level.

Legal entity responsible for the study

Hans Wildiers.

Funding

FWO.

Disclosure

All authors have declared no conflicts of interest.

中文翻译：

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三种不同年龄类别的管腔乳腺癌中133P肿瘤免疫浸润的特征及其与虚弱的关系

抽象的

背景

免疫衰老是与年龄相关的免疫能力下降的特征，其特征在于适应性免疫力下降和低度炎症增加。这可能导致抗肿瘤免疫反应改变，从而影响老年癌症患者的肿瘤免疫浸润。然而，尚未在衰老的背景下对乳腺癌（BC）进行详细的肿瘤浸润表征。

方法

这项探索性研究调查了早期BC（I-III级，ER +，HER2-级）患者肿瘤微环境中与年龄相关的变化。患者分为三个年龄段：35-45岁（y）（N = 15），55-65y（N = 19），≥70y（N = 31）。根据已发布的指南评估间质肿瘤浸润淋巴细胞（sTILs）的百分比。通过使用QuPath软件使用新开发的分析流程确定CD68等级并评分其他免疫标记（CD3，CD4，CD5，CD8，CD20和FOXP3），建立了免疫浸润特性。在年龄最大的组中，获得老年8（G8）评分作为临床虚弱水平的相关指标。

结果

随着年龄的增长，sTILs百分比显着降低，同时在整个肿瘤区域中的T细胞（CD3 ⁺和CD5 ⁺），细胞毒性T细胞（CD8 ⁺）和B细胞（CD20 ⁺）密度显着降低。当分别评估肿瘤区域时，观察到侵袭性前沿（CD3 ⁺，CD5 ⁺，CD8 ⁺，CD20 ⁺细胞）和肿瘤中心（CD3 ⁺，CD5 ⁺，CD8 ⁺细胞）免疫细胞密度的明显年龄相关性下降。CD4 ⁺和FOXP3 ⁺没有发现与年龄相关的变化细胞浸润或肿瘤中CD68级。G8评分与肿瘤中心的调节性T细胞（FOXP3 ⁺）密度呈显着负相关。然而，免疫细胞群的空间分布并不取决于年龄或脆弱水平。

结论

总之，在年轻和年长的BC患者中，肿瘤中几种免疫标记物的sTILs百分比和密度显着不同。此外，体弱患者的调节性T细胞密度较高（G8评分较低）。这可能表明这些患者的肿瘤免疫反应可能不太有效，并且免疫治疗的方法可能会根据患者的年龄/身体虚弱程度而有所不同。

负责研究的法人实体

汉斯·怀尔德（Hans Wildiers）。

资金

四个

揭露

所有作者均声明没有利益冲突。