Invariant natural killer T cells coordinate removal of senescent cells

BackgroundThe failure of immune surveillance to remove senescent cells drive age-related diseases. Here, we target an endogenous immune surveillance mechanism that can promote elimination of senescent cells and reverse disease progression.MethodsWe identify a class of lipid-activated T cells, invariant natural killer T cells (iNKTs) are involved in the removal of pathologic senescent cells. We use two disease models in which senescent cells accumulate to test whether activation of iNKT cells was sufficient to eliminate senescent cells in vivo.FindingsSenescent preadipocytes accumulate in white adipose tissue of chronic high-fat diet (HFD) fed mice, and activation of iNKT cells with the prototypical glycolipid antigen alpha-galactosylceramide (αGalCer) led to a reduction of these cells with improved glucose control. Similarly, senescent cells accumulate within the lungs of mice injured by inhalational bleomycin, and αGalCer-induced activation of iNKT cells greatly limited this accumulation, decreased the lung fibrosis and improved survival. Furthermore, co-culture experiments showed that the preferential cytotoxic activity of iNKT cells to senescent cells is conserved in human cells.ConclusionsThese results uncover a senolytic capacity of tissue-resident iNKT cells and pave the way for anti-senescence therapies that target these cells and their mechanism of activation

Abstract C036: Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers

Abstract: The stroma that surrounds the tumor in many solid cancers exhibits potent immunosuppressive activity to promote tumor progression and confer resistance to immune-based therapies. Cancer associated fibroblasts (CAFs) encompassing functionally distinct populations are key components of the stroma that are emerging as a key cell type in regulating an immune response. However, the mechanisms by which CAFs can directly suppress the immune activity to promote tumor growth is not clear. Here, we identify that a subset of CAF in both rodent and human stromagenic cancers that displays characteristics of senescent fibroblasts and referred to as sCAFs. We show that sCAFs secrete a decoy protein that interferes with cytotoxic activity of activated T effector (Teff) cells. In mouse models for stroma-rich pancreatic cancer, administration of an antibody that blocked the decoy protein resulted in recalibration of the stromal fibroblast by promoted the formation of interferon-licensed-fibroblast cells at the expense of sCAFs. This switch not only enhanced infiltration of tumor-infiltrating T cells but also alleviated their direct suppression resulting in enhanced effector function and tumor regression. Collectively, these results point to the potent immunosuppressive activity of sCAFs mediated by decoy protein as a mechanism by which stroma can promote tumor progression. As stromagenic-cancers are resistance to current therapies, the development of treatments involving blocking of decoy protein may inhibit tumor growth and improve patient survival. Citation Format: Yao Wang, Hara Apostolopoulou, Arjun Sanyal, Hong Sun, Cynthia Sieland, Kavya Gupta, Jiayu Ye, David Gibbs, Paul Wong, Ntranos Vasilis, Sui Huang, James Gardner, Ajay Maker, Thea Tlsty, Anil Bhushan, Tamara Alliston. Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C036

Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion

Malignant pleural effusion (MPE) is a life-threatening cancer-related disorder. Here, the authors show that KRAS-mutant tumor cells require IKKα, activated via host-provided IL-1β, to promote MPE development and that co-inhibition of both KRAS and IKKα ameliorates the development of MPE in mouse models

Mast cells mediate malignant pleural effusion formation

Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1 beta, which in turn induced pleural vasculature leakiness and triggered NF-kappa B activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenbcarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable