Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition.

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Understanding immune escape mechanisms is crucial for developing effective cancer immunotherapies.
• Breast tumor progression involves complex interactions between cancer cells and the immune microenvironment.

Purpose of the Study:

• To analyze leukocyte composition and immune cell signatures during breast cancer progression from normal tissue to ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDC).
• To identify immune regulators and genomic alterations associated with immune escape and tumor evolution.

Main Methods:

• Analysis of leukocyte composition in normal breast tissue, DCIS, and IDC.
• Gene expression profiling of T cells.
• Immunofluorescence analysis of activated CD8+ T cells (GZMB+).
• T-cell receptor clonotype diversity analysis.
• Assessment of immune checkpoint protein expression (TIGIT, PD-L1) and gene amplification (CD274).

Main Results:

• Significant differences in leukocyte composition, including T cells and neutrophils, were observed across tissue types and tumor subtypes.
• Invasive ductal carcinomas (IDCs) showed decreased CD8+ T cell signatures and fewer activated GZMB+ CD8+ T cells compared to DCIS.
• T-cell receptor clonotype diversity was higher in DCIS than in IDCs.
• TIGIT-expressing T cells were more frequent in DCIS, while high PD-L1 expression and CD274 amplification were found in triple-negative IDCs.
• Coamplification of a 17q12 chemokine cluster with ERBB2 defined distinct subtypes within HER2+ breast tumors.

Conclusions:

• Breast cancer progression is characterized by a transition to a less immunologically active tumor microenvironment.
• Immune escape mechanisms involve changes in T cell activity, immune checkpoint expression, and genomic alterations.
• These findings provide insights into tumor evolution and can inform the design of targeted cancer immunotherapies.