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 MicroenvironmentABSTRACT
From September 20 to 23, 2023, the Seventh International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the European Network for Cancer Immunotherapy (ENCI), and the American Association for Cancer Research (AACR) in Milan, Italy. The four-day event covered the latest advances in cancer immunology and immunotherapy.
Subject(s)
Neoplasms , Humans , Neoplasms/therapy , ImmunotherapyABSTRACT
The 19th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Europe's cancer immunotherapy meeting, was the first in-person event organized by CIMT since the beginning of the COVID-19 pandemic. As a hybrid event from May 10-12, the meeting attracted 920 academic and clinical professionals from over 40 countries, who met to discuss the latest advances in cancer immunology and immunotherapy research. This report summarizes the highlights of CIMT2022.
Subject(s)
COVID-19 , Neoplasms , Humans , Pandemics , Neoplasms/therapy , COVID-19/therapy , Immunotherapy , Tumor MicroenvironmentABSTRACT
Synthetic mRNA provides a template for the synthesis of any given protein, protein fragment or peptide and lends itself to a broad range of pharmaceutical applications, including different modalities of cancer immunotherapy. With the ease of rapid, large scale Good Manufacturing Practice-grade mRNA production, mRNA is ideally poised not only for off-the shelf cancer vaccines but also for personalized neoantigen vaccination. The ability to stimulate pattern recognition receptors and thus an anti-viral type of innate immune response equips mRNA-based vaccines with inherent adjuvanticity. Nucleoside modification and elimination of double-stranded RNA can reduce the immunomodulatory activity of mRNA and increase and prolong protein production. In combination with nanoparticle-based formulations that increase transfection efficiency and facilitate lymphatic system targeting, nucleoside-modified mRNA enables efficient delivery of cytokines, costimulatory receptors, or therapeutic antibodies. Steady but transient production of the encoded bioactive molecule from the mRNA template can improve the pharmacokinetic, pharmacodynamic and safety properties as compared to the respective recombinant proteins. This may be harnessed for applications that benefit from a higher level of expression control, such as chimeric antigen receptor (CAR)-modified adoptive T-cell therapies. This review highlights the advancements in the field of mRNA-based cancer therapeutics, providing insights into key preclinical developments and the evolving clinical landscape.
