The British Society for Immunology (BSI) Congress 2021 took place from 28 November to 1 December 2021 online and in-person in Edinburgh, UK. A primary aim of the Myrovlytis Trust is advancing research into immunotherapies and new routes to treatment for rare cancers, focusing on osteosarcoma. As the UK’s largest immunology event, the Myrovlytis Trust were thrilled to be able to attend and listen to the latest updates in cancer immunology.
Of particular interest was the session entitled ‘The Unique immunological landscape of the tumour microenvironment’ with talks focusing on different immune cells, their pro- and anti-cancer roles, and importantly how they can be harnessed to target cancer and improve responses to immunotherapies. Several talks focused on the role tertiary lymphoid structures (TLS) play in the response to immunotherapies. Catherine Sautés-Fridman (University de Paris, Centre de Recherche des Cordeliers, France) opened the session presenting her work on the interplay between TLS and B cells. Her research demonstrated that the presence of TLS in tumours correlated with B cell infiltration, which in turn indicated a better response to immunotherapy and overall prognosis in several cancers, including soft-tissue sarcomas (1). This was corroborated further by Karen Willard-Gallo (Institut Jules Bordet, Belgium) whose work in triple negative breast cancer also revealed the importance of an active TLS and B cell infiltration resulting in reduced disease progression and increased survival rates (2). However, work needs to be done to understand how to induce activity of TLS to improve the prognosis in individuals with tumours that lack high density, active TLS.
Another session with key relevance to the Myrovlytis Trust was ‘Defining the state and functional relevance of T cell exhaustion’ with talks from Andrea Schietinger (Memorial Sloan Kettering Cancer Center, USA), Benjamin Youngblood (St. Jude Children’s Research Hospital, USA) and Dietmar Zehn (Technical University of Munich, Germany). T cell exhaustion, a common state of T cell dysfunction found in many cancers, is defined by poor effector function. Understanding the mechanism by which T cells display an exhaustion phenotype and lose their effector function is critical to be able to restore T cell-mediated anti-cancer immunity. Andrea Schietinger’s lab took an innovative approach to this and studied T cells in the context of autoimmunity in which T cells remain highly functional in the presence of chronic antigen stimulation. In a mouse model of type 1 diabetes (resulting in CD8 T cell-mediated killing of pancreatic cells) she discovered a population of T cells with ‘stem cell-like’ properties which had the ability to self-renew and lead to terminally differentiated populations (3). Adoptive transfer of as few as 10 of these stem cell-like T cells led to the induction of type 1 diabetes, indicating the power of this pool of cells. The challenge now, however, is to be able to apply this principle in cancer, perhaps through reprogramming of autoimmune T cells using cancer-specific T cell transcription factors. CAR T cell therapy has the potential to revolutionise cancer treatment. However, these T cells also suffer from exhaustion, and the ability of CAR T cells to persist is critical for their success as an anti-cancer therapy. Epigenetic modification can alter the gene expression profile of a cell, and therefore can modulate T cell exhaustion. Benjamin Youngblood identified a DNA methyltransferase, DNMT3A, which when deleted from CAR T cells allowed enhanced survival, proliferation and activity in the context of chronic antigen presentation. In a mouse model of osteosarcoma, mice that received DNMT3A knockout CAR T cells exhibited a significant survival advantage over mice that received control CAR T cells (4).
Finally, the session entitled ‘Advances in cancer immunology: bringing two communities together’ highlighted the work of Sophie Papa (King’s College London, UK) who’s research focuses on CAR T cell therapy in solid tumours and how translation of this technology to the clinic can be enhanced. Trials for CAR T cell therapy in solid tumours have shown limited efficacy in patients and there is desperate need for enhancement of this for CAR T cell therapy to progress to the clinic. Understanding the metabolic factors that influence the efficacy of CAR T cells is one area of interest, as Dr Papa highlighted the artificially high levels of glucose cells are cultured in in vitro. Lowering the levels of glucose in culture media led to a reduction in effectiveness of PSMA-targeting CAR T cells through a lack of proliferation. Understanding these mechanisms will undoubtedly reveal novel strategies to enhance CAR T cell therapy and facilitate its progression to the clinic in a wider range of cancers.
Take Home Messages
Understanding of the tumour microenvironment and the role of immune cells in cancer is a rapidly changing field. Advances in technologies such as single cell RNA sequencing allow detailed mapping of changes occurring within individual cells. However, studies characterising the immune-cancer microenvironment are only the first step and research now needs to progress to identify how to harness the power of immune cells in tumours to reprogramme or enhance their anti-cancer properties. Areas of research presented at the BSI congress that are of great interest to the Myrovlytis Trust included inducing the activity of TLS, metabolic reprogramming of immune cells, and reprogramming T cells to prevent an exhaustion phenotype.
The Myrovlytis Trust is committed to advancing research into immunotherapies for rare conditions to rapidly bring novel and effective treatments to the clinic. We are open to discussions with clinicians and researchers about their work to identify ways in which we can support your research. Please visit our website for more information on our funding streams or contact us by email.
1. Petitprez F, de Reyniès A, Keung EZ, Chen TWW, Sun CM, Calderaro J, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nat 2020 5777791 [Internet]. 2020 Jan 15 [cited 2021 Dec 9];577(7791):556–60. Available from: https://www.nature.com/articles/s41586-019-1906-8
2. Boisson A, Noël G, Saiselet M, Rodrigues-Vitória J, Thomas N, Fontsa ML, et al. Fluorescent Multiplex Immunohistochemistry Coupled With Other State-Of-The-Art Techniques to Systematically Characterize the Tumor Immune Microenvironment. Front Mol Biosci [Internet]. 2021 Sep 21 [cited 2021 Dec 9];8. Available from: https://pubmed.ncbi.nlm.nih.gov/34621785/
3. Gearty S V., Dündar F, Zumbo P, Espinosa-Carrasco G, Shakiba M, Sanchez-Rivera FJ, et al. An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature [Internet]. 2021 Nov 30 [cited 2021 Dec 9]; Available from: https://pubmed.ncbi.nlm.nih.gov/34847567/
4. Prinzing B, Zebley CC, Petersen CT, Fan Y, Anido AA, Yi Z, et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci Transl Med [Internet]. 2021 Nov 17 [cited 2021 Dec 9];13(620). Available from: https://www.science.org/doi/abs/10.1126/scitranslmed.abh0272