Abstract
Immune-based anti-cancer strategies combined with radiation therapy (RT) are actively being investigated but many questions remain, such as the ideal treatment scheme and whether a potent immune response can be generated both locally and systemically. In this context, tumor-associated tertiary lymphoid structures (TLS) have become a subject of research. While TLS are present in several types of cancer with strong similarities, they are especially relevant in medullary breast carcinoma (MBC). This suggests that MBC patients are ideally suited for investigating this question and may benefit from adapted therapeutic options. As RT is a corner-stone of MBC treatment, investigating interactions between RT and TLS composition is also clinically relevant. We thus first characterized the lymphoid structures associated with MBC in a patient case report and demonstrated that they closely resemble the TLS observed in a genetical mouse model. In this model, we quantitatively and qualitatively investigated the cellular composition of the tumor-associated TLS. Finally, we investigated TLS regulation after hypo-fractionated RT and showed that RT induced their acute and transient depletion, followed by a restoration phase. This study is the first work to bring a comprehensive and timely characterization of tumor-associated TLS in basal conditions and after RT. It highlights cellular targets (i.e., Tregs) that could be selectively modulated in subsequent studies to optimize anti-tumor immune response. The study of TLS modulation is worth further investigation in the context of RT and personalized medicine.
Highlights
Medullary breast carcinoma (MBC) is a unique and curious subtype of infiltrating ductal carcinoma first described in 1945 [1]
Showed that only 13.5% of medullary breast carcinoma (MBC) patients had LN metastasis. It appeared that MBC was less prone to metastatic development and had a relatively good prognosis, despite its epithelial grade and molecular profile status
Recent work has challenged this notion of a favorable prognosis [3] and radio-chemotherapy remains the standard of care for these patients [4], at the costly risk, of over-treating young patients
Summary
Medullary breast carcinoma (MBC) is a unique and curious subtype of infiltrating ductal carcinoma first described in 1945 [1]. In 1977, Ridolfi et al published a study with 10 years longitudinal follow-up on MBC and TLS Contribution to RT showed that only 13.5% of MBC patients had LN metastasis. From this seminal study, it appeared that MBC was less prone to metastatic development and had a relatively good prognosis, despite its epithelial grade and molecular profile status. It was speculated early on that this paradox was linked to the typical lymphoplasmatic intra-tumor infiltration and/or the presence of tertiary lymphoid structures (TLS) at the vicinity of MBC [2]. Recent work has challenged this notion of a favorable prognosis [3] and radio-chemotherapy remains the standard of care for these patients [4], at the costly risk, of over-treating young patients
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