Leveraging Radiation-Induced Senescence and PTPN2 Inhibition to Enhance Immune-Mediated Tumor Control in Rectal Cancer

Project Summary Rectal cancer (RC) incidence is rising among young adults and is now among the leading cause of cancer deaths among people under 50 years old. Treatment for RC typically involves trimodality therapy— chemoradiation, chemotherapy, and surgery—which can lead to significant lifelong morbidity. This is especially significant for patients with low rectal tumors, as surgical removal of the anus and rectum results in a permanent colostomy. Therefore, there is an urgent need for non-surgical treatment strategies that prioritize organ preservation to minimize lifelong morbidities. While radiation therapy (RT) has traditionally been understood to exert its effects primarily via DNA damage, recent evidence emphasizes the critical role of immune-mediated, tumor-extrinsic mechanisms in shaping tumor response. A potential mediator of these effects is radiation-induced senescence (RIS)—a stress-response program characterized by durable cell cycle arrest, the immunomodulatory senescence-associated secretory phenotype (SASP), and the surface remodeling that alters tumor-immune cell interactions. Our preliminary data demonstrated that RIS and SASP not only remodel the tumor immune microenvironment (TIME) but also activate anti-tumor immune surveillance programs, thereby enhancing RT efficacy. In RC and melanoma models, RIS and SASP significantly increased immune engagement and tumor radiosensitivity. Notably, combining RT with PTPN2 inhibition (PTPN2i) further potentiated these effects, leading to robust immune responses and superior survival outcomes compared to RT + PD-1 blockade. Our pilot analyses of human RC samples revealed RIS, SASP, and immune signatures post-RT, underscoring the therapeutic potential of targeting RIS and SASP, especially in combination with PTPN2i. Utilizing our innovative murine and patient-derived organoid RC models, longitudinal patient samples, and cutting-edge single-cell and spatial profiling technologies optimized for senescence research, we are well positioned to address the following specific aims: AIM 1: Dissect the impact of RIS on the tumor immune microenvironment and therapeutic outcome. AIM 2: Leverage PTPN2i to potentiate response to RT. AIM 3: Characterize RIS and SASP programs and PTPN2i potentiation in human RC organoid models and longitudinal patient specimens. This project will elucidate the mechanisms by which RIS and SASP modulate the immune response, will explore a novel therapeutic strategy combining RT and PTPN2i, and will provide the most detailed characterization of RIS in humans to date. These findings will pave the way for early-phase clinical trials of RT combined with PTPN2i, potentially transforming the treatment paradigm in RC by enabling organ-preserving therapies and improving clinical outcomes. Moreover, the insights gained could have broad applicability across other cancer types.