Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4 T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the or oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4 T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction. ► Oncogene addiction involves both cell autonomous and nonautonomous mechanisms ► An immune system is required for sustained tumor regression upon inactivation of oncogenes ( or ) ► CD4 T cells regulate cellular senescence and angiogenesis in the tumor microenvironment ► TSP-1 secretion from immune cells is required for sustained tumor regression upon inactivation of an oncogene
Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.
Acidic extracellular pH is a major feature of tumor tissue, extracellular acidification being primarily considered to be due to lactate secretion from anaerobic glycolysis. Clinicopathological evidence shows that transporters and pumps contribute to H+ secretion, such as the Na+/H+ exchanger, the H+-lactate co-transporter, monocarboxylate transporters, and the proton pump (H+-ATPase); these may also be associated with tumor metastasis. An acidic extracellular pH not only activates secreted lysosomal enzymes that have an optimal pH in the acidic range, but induces the expression of certain genes of pro-metastatic factors through an intracellular signaling cascade that is different from hypoxia. In addition to lactate, CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment. In this article, the importance of an acidic extracellular pH as a microenvironmental factor participating in tumor progression is reviewed.
Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-kappa B dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-kappa B by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.
How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8 TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8 TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8 TILs' antigen specificity. Further promoting FA catabolism improves the CD8 TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures. Zhang et al. show that CD8 T cells enhance PPAR-α signaling and fatty acid catabolism under the hypoglycemic and hypoxic condition to partially preserve effector functions. Metabolic reprogramming of T cells using a PPAR-α agonist improves tumor growth control, which is enhanced in combination with PD-1 blockade.
Tumor development is a Darwinian evolutionary process, involving the interplay between cancer subclones and the local immune microenvironment. These complex interactions are highlighted in this issue of by the results from Jiménez-Sánchez et al. of a deep analysis of one patient with advanced serous carcinoma of the ovary. Tumor development is a Darwinian evolutionary process, involving the interplay between cancer subclones and the local immune microenvironment. These complex interactions are highlighted in this issue of by the results from Jiménez-Sánchez et al. of a deep analysis of one patient with advanced serous carcinoma of the ovary.
Vascularization is a critical step in the restoration of cellular homeostasis. Several strategies including localized growth factor delivery, endothelial progenitor cells, genetically engineered cells, gene therapy, and prevascularized implants have been explored to promote revascularization. But, long‐term stabilization of newly induced vessels remains a challenge. It has been shown that fibroblasts and mesenchymal stem cells can stabilize newly induced vessels. However, whether an injected biomaterial alone can serve as an instructive environment for angiogenesis remains to be elucidated. It is reported here that appropriate vascular branching, and long‐term stabilization can be promoted simply by implanting a hydrogel with stiffness matching that of fibrin clot. A unique subpopulation of circulating CD11b + myeloid and CD11b + /CD115 + monocytes that express the stretch activated cation channel Piezo‐1, which is enriched prominently in the clot‐like hydrogel, is identified. These findings offer evidence for a mechanobiology paradigm in angiogenesis involving an interplay between mechanosensitive circulating cells and mechanics of tissue microenvironment. Neovasculature is vital for tissue repair and regeneration. In this study, the induction and stabilization of blood vessels by simply injecting a biomaterial of defined mechanical properties is reported. A hitherto unknown population of circulating monocytes positive for mechanosensing protein Piezo‐1, which is recruited de novo in vessel maturation, is identified, thus elaborating a role for mechanobiology in vascular stabilization.