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Unravelling the Immune Landscape of Rectal Cancer in the Neoadjuvant Setting

par Iliadi Anagnostaki, Chrysanthi
Président du jury Langer, Ingrid
Promoteur Penninckx, Sébastien
Co-Promoteur Sclafani, Francesco
Publication Non publié, 2026-01-27

Thèse de doctorat

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Résumé :

Rectal cancer is the seventh most common cancer in Europe, and its incidence is on the rise in young adults (<50 years). Standard treatment for locally advanced tumors generally includes neoadjuvant therapy (short-course radiotherapy (SCRT), long-course chemoradiotherapy (CRT) or total neoadjuvant therapy (TNT)) followed by surgery with or without adjuvant chemotherapy. A significant proportion of tumors do not respond to neoadjuvant therapy. The tumor immune microenvironment (TIME) plays a critical role in shaping treatment responses and at the same time treatment-related alterations can serve as indicators for disease progression. Despite advances in characterizing the TIME, there is still a gap in our knowledge of how the local immune response is shaped by neoadjuvant therapy in rectal cancer patients. This thesis aimed to study the changes in the immune landscape of rectal tumors in relation to radiotherapy within the neoadjuvant setting and correlate immune cell composition with distinct clinical outcomes. In the first chapter, we designed, optimized, and automated the staining of three multiplex immunohistochemistry panels for the analysis of the rectal tissue tumor microenvironment. In the second chapter, we characterized the immune landscape of rectal cancer across four neoadjuvant treatment strategies: neoadjuvant chemoradiotherapy (nCRT), neoadjuvant chemotherapy alone (nCT), neoadjuvant radiotherapy alone (nRT) and surgery without any preoperative therapy (no noNAT). We observed that the tumor microenvironment exhibited treatment-specific differences, with CD20+ B cells significantly reduced in irradiated tumors, while macrophages and CD47⁺ cells remained consistently abundant, reflecting a predominantly immunosuppressive landscape. 15 Subsequently, in chapter 3, we focused on the chemoradiotherapy group of patients that was the largest group, and we compared the immune landscape in responders versus non-responders patients and recurrent versus non-recurrent. CD8⁺ T cell densities were comparable across the response groups. Macrophages dominated the TIME and were enriched in non-responders, while CD163⁺ macrophages trended higher in the latter group of patients. Patients with recurrence had significantly higher levels of T regulatory cells, suggesting an immunosuppressive TIME. Collectively, these findings provide new insights into the tumor microenvironment of rectal cancer patients in the neoadjuvant settings. Our research identifies a macrophage-enriched, immunosuppressive TIME as a hallmark of resistance to nCRT and recurrence in rectal cancer. These findings support the inclusion of macrophage-specific analysis in future clinical trial designs and demonstrate clinical utility of immune profiling.