ABSTRACT
Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses. SIGNIFICANCE: Our study shows that senescent cells are endowed with a high immunogenic potential-superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses. See related article by Chen et al., p. 432. This article is highlighted in the In This Issue feature, p. 247.
Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Mice , Animals , Humans , Mice, Inbred C57BL , CD8-Positive T-Lymphocytes/immunology , Cellular Senescence , Tumor MicroenvironmentABSTRACT
Gain-of-function mutations of kit tyrosine kinase receptor are associated with mastocytosis. Two subclones of the HMC1 mast leukaemia cell line were used; both express an identical KIT allele-specific regulatory type mutation (V560G), but differ in that one also expresses an enzymatic site type mutation (D816V) that confers on them resistance to imatinib mesylate tyrosine kinase inhibitor. In both cell lines, proliferation was suppressed and apoptosis induced by the combination of KIT gene silencing and alpha-tocopherol succinate (alpha-TOS), a derivate of alpha-tocopherol, also known as vitamin E. Furthermore, HMC1 cells with decreased kit levels by KIT silencing, failed to form tumours when xenotransplanted into immunocompromised mice and the animals were treated systemically with alpha-TOS. Targeting kit in the presence of alpha-TOS represents a new approach against proliferation of human mast leukaemia cell lines.
Subject(s)
Genetic Therapy/methods , Mastocytosis/therapy , Proto-Oncogene Proteins c-kit/genetics , alpha-Tocopherol/therapeutic use , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Transformation, Neoplastic/genetics , Combined Modality Therapy , Gene Knockdown Techniques , Gene Silencing , Humans , Mastocytosis/pathology , Mice , Mice, Nude , Mutation , Neoplasm Transplantation , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
The proto-oncogene c-kit plays an important role in the development and survival of mast cells. Gain-of-function mutations in c-kit are one of the most characteristic events in mast cell leukemia (MCL) but as yet there is no clinically approved treatment for the disease. Here we describe growth inhibition of human MCL cell lines by the use of RNAi against c-kit or its mutant form. Retroviral transduction of HMC1.1 and HMC1.2 cell lines with vectors carrying DNA to be transcribed to RNAi against the wild type or mutant c-kit messengers reduced Kit protein levels considerably, decreased cell proliferation, and increased the apoptotic levels five days after retroviral infection. Thus RNAi targeted against Kit or its mutant form could be considered as a new antiproliferative agent against human mast leukemia cell lines, especially HMC1.2 cells which are resistant to the Kit tyrosine kinase inhibitor, imatinib mesylate.
