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1.
Cancer Cell ; 42(4): 568-582.e11, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38490213

ABSTRACT

Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying ß2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8+ T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.


Subject(s)
CD8-Positive T-Lymphocytes , Neoplasms , Animals , Mice , Histocompatibility Antigens Class I/genetics , Interleukin-2/genetics , Interleukin-2/immunology , Neoplasms/genetics , RNA, Messenger , Tumor Microenvironment
2.
Science ; 371(6525): 145-153, 2021 01 08.
Article in English | MEDLINE | ID: mdl-33414215

ABSTRACT

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.


Subject(s)
Bystander Effect/immunology , Encephalomyelitis, Autoimmune, Experimental/therapy , Immunosuppression Therapy/methods , Multiple Sclerosis/therapy , Vaccines, Synthetic/therapeutic use , Animals , Antigen-Presenting Cells , Autoantigens/genetics , Inflammation/immunology , Mice , Mice, Inbred C57BL , Pseudouridine/analogs & derivatives , Pseudouridine/chemistry , RNA, Messenger/adverse effects , RNA, Messenger/chemistry , RNA, Messenger/genetics , T-Lymphocytes, Regulatory/immunology , Vaccines, Synthetic/adverse effects , mRNA Vaccines
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