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Recombinant Listeria promotes tumor rejection by CD8 + T cell-dependent remodeling of the tumor microenvironment
- Source :
- Proceedings of the National Academy of Sciences. 115:8179-8184
- Publication Year :
- 2018
- Publisher :
- Proceedings of the National Academy of Sciences, 2018.
-
Abstract
- Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L− CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206− M1 phenotype. Remarkably, these LADD-Ag–induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells.
- Subjects :
- 0301 basic medicine
Tumor microenvironment
Multidisciplinary
Chemistry
medicine.medical_treatment
Priming (immunology)
Immunotherapy
medicine.disease
Primary tumor
Immune checkpoint
3. Good health
03 medical and health sciences
030104 developmental biology
Antigen
Cancer research
medicine
Cytotoxic T cell
CD8
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi...........f4a25b932352433246ab238e19aa57e3