Varshitha Dhulipala

Background: Hodgkin’s Lymphoma (HL) is a B-cell lymphoid malignancy affecting about 8,000 new patients annually. It has a bimodal distribution in terms of the ages of patients, with diagnoses more commonly being made in children and older adults¹. Radiation therapy is often aimed at the lymph nodes that show lymphadenopathy, which are most commonly around the chest area, and the major side effect is irradiation of the breast tissue. Therefore, childhood HL treatment has been associated with secondary breast cancer later in life, and it is becoming increasingly important to understand the mechanism of this phenomenon².

Objective: This review aims to find markers in radiation-preceded breast cancer tumors that could elucidate the mechanism by which secondary breast cancer develops years later in young HL patients.

Search Methods: An online search in the PubMed database was conducted from 2018 forward for keywords such as “secondary breast cancer,” “TGF-β,” “microenvironment,” and “HL.”

Results: Studies show that the tumor microenvironment (TME) of radiation-preceded breast cancer (RPBC) contains a mix of pro-inflammatory (IL6, TNF, matrix metalloproteinases, lysyl oxidase) and anti-inflammatory (CD163+ M2 macrophages, IL10, TGF-β, mast cells) factors³. However, even the anti-inflammatory factors function to create an immunosuppressive TME where T-cells can’t penetrate the irradiated area. Programmed death ligand 1 (PD-L1) is a ligand that is correlated with worsened RPBC prognosis. High levels of PD-L1 are associated with macrophage infiltration and anti-inflammatory cytokines, leading to extracellular matrix remodeling, increased collagen production, and matrix-degrading enzymes, which reinforces physical and immunological barriers to leukocyte infiltration⁴. Another important cytokine is TGF-β, and it regulates monocyte differentiation to suppress cytotoxic T-cells, leading to an immunologically depressed TME. Furthermore, TGF-β signals nearby fibroblasts to deposit more collagen into the stroma, and the increased fibers act as a physical barrier, effectively blocking T-cell infiltration and further leading to an immunosuppressed TME^5,6. Studies have also shown that some patients with the C-509T polymorphism on the TGF-β promoter produce more TGF-β and have an increased risk for developing fibrosis after chest irradiation⁷. Furthermore, studies showed that blocking the production of TGF-β during radiation therapy can reduce the chances of developing secondary breast cancer or could at least decrease the severity⁸.

Conclusions: Studies have shown that RPBC is associated with higher levels of PD-L1 and TGF-β. Furthermore, those with the C-509T polymorphism on the TGF-β promotor have an increased risk of fibrosis and development of RPBC. While TGF-β is normally an anti-inflammatory cytokine, its presence, particularly having too much, can lead to the development of an immunosuppressive environment. PD-L1 contributes to sustaining the TME by degrading the existing ECM and causing the deposition of more collagen in a way to increase fibrosis and prevent lymphocytes from accessing that area. This environment does not necessarily cause tumorigenesis, but it decreases the chance of cytotoxic T-cells being able to remove transformed cells, leading to an increased risk of cancer development later in life. With this information, it can be beneficial to screen patients for the C-509T polymorphism to evaluate if HL patients are at higher risk of developing RPBC or considering blocking TGF-β during radiation therapy.

Works Cited:

1. Ansell SM. Hodgkin lymphoma: 2025 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024;99(12):2367-2378. doi:10.1002/ajh.27470
2. Laddaga FE, Telegrafo M, Garzillo C, et al. Long-Term Breast Cancer Risk in Hodgkin Lymphoma Survivors: Evaluating Background Parenchymal Enhancement and Radiotherapy-Induced Toxicity. Cancers (Basel).
3. Ma L, Gonzalez-Junca A, Zheng Y, et al. Inflammation Mediates the Development of Aggressive Breast Cancer Following Radiotherapy. Clin Cancer Res. 2021;27(6):1778-1791. doi:10.1158/1078-0432.CCR-20-3215
4. Chekhun V, Lukianova Y, Mushii O, et al. Breast cancer microenvironment composition associated with high PD-L1 expression. BMC Cancer. 2026;26(1):217. Published 2026 Jan 14. doi:10.1186/s12885-026-15542-0
5. Gonzalez-Junca A, Driscoll KE, Pellicciotta I, et al. Autocrine TGFβ Is a Survival Factor for Monocytes and Drives Immunosuppressive Lineage Commitment. Cancer Immunol Res. 2019;7(2):306-320. doi:10.1158/2326-6066.CIR-18-0310
6. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544-548. doi:10.1038/nature25501
7. Grossberg AJ, Lei X, Xu T, et al. Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018;4(12):1751-1757. doi:10.1001/jamaoncol.2018.2583
8. Formenti SC, Lee P, Adams S, et al. Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer. Clin Cancer Res. 2018;24(11):2493-2504. doi:10.1158/1078-0432.CCR-17-3322