Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

Abstract

More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC.

Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming

“…More evidence suggests that post-senescence stemness reprograming is also applicable in other solid tumors. It is not unique that after chemotherapy, the expression of stem-related molecules such as EpCAM, CD326, CD24, and NANOG increased in hematological tumors, liver cancer cells [ 21 ], pancreatic cancer cells, colon cancer cells, and peritoneal metastasis cells [ 46 ] ( Figure 1 ). According to studies of lung cancer model survival after radiation therapy, compared to surviving cells that received the same dose of radiation (6 times), lung cancer cells that survived after 3 doses of radiation therapy strongly expressed stem-related signals, such as CD44, CD133, and OCT4, and were associated with increased senescence-related SA-β-Gal staining [ 47 ].…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…The SASP of senescent cancer cells enhanced immunosenescence (immune suppression) in the TME of peritoneal carcinomatosis (PC) to promote tumor progression [ 97 ]. Doxorubicin-induced senescence promoted the recruitment of Treg cells and myeloid-derived suppressor cells to mediate apoptotic resistance in diffuse large B-cell lymphoma (DLBCL) via pro-inflammatory cytokines, such as IL-2, IL-6, IL-8, IL-10, IL-35, TGFβ, and VEGF [ 77 ].…”

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

“…Contrarily, senescent cancer cells have been found to support tumor spread in CRC [190]. Exploiting both human and mouse samples, Braumüller et al showed that SASP factors may lead to enhanced immuno-senescence in the TME of CRC, thus explaining its resistance to known chemo-and immunotherapeutic approaches [191]. Indeed, the authors showed that senescent cancer cells acquired a stem cell-like phenotype in both murine and human samples, possibly leading to deleterious consequences, like chemotherapy resistance.…”