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Singleron Publications 2024
Singleron Publications 2024

2024 in Review: A Year of Remarkable Scientific Breakthroughs 

5’
Immunology Oncology Review

What a year 2024 has been for the scientific community – in particular in the field of immuno-oncology! Researchers using Singleron’s products have collectively published over 150 studies this year, each one pushing the boundaries of our understanding of diseases and molecular mechanisms. We are immensely proud to celebrate the dedication and success of these brilliant scientists whose work continues to inspire and drive progress in the field. 

As we bid farewell to 2024, it’s the perfect time to reflect on some of the outstanding publications that made this year so impactful: 

The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer (Feng B. et al., Nature. 2024): 

How can we make cancer treatment more effective? Current cancer immunotherapy primarily targets tumors through type 1 immune responses, which are effective but rarely achieve long-term remission. Overactivation of type 1 immunity can cause inflammation. This highlights the need for balanced strategies incorporating other immune pathways, such as type 2 responses. 

Researchers from Lausanne University investigated the potential of Fc–IL-4, a type 2 cytokine-based therapy, to enhance cancer treatment. Fc–IL-4 synergizes with type 1-focused therapies like adoptive T cell transfer (ACT) and immune checkpoint blockade (ICB) to overcome tumor resistance and relapse. It directly acts on terminally exhausted CD8+ T cells (CD8+ TTE), boosting their survival, cytotoxicity, and glycolytic metabolism in an LDHA-dependent manner. 

Single cell RNA sequencing (scRNA-seq) revealed that Fc–IL-4 enriched clusters of CD8+ TTE cells expressed high levels of functional genes like Ifng (interferon-gamma) and Gzmb (granzyme B) (Figure 1). Additional profiling identified metabolic and transcriptional changes, particularly in glycolysis. Fc–IL-4 therapy achieved durable tumor remission and immune memory in multiple models. This paves the way for a novel strategy to integrate type 1 and type 2 immunity for next-generation cancer therapies. 

Figure 1: Single cell sequencing analysis reveals that Fc–IL-4 selectively amplifies the CD8+ TTE cell population while enhancing their effector function in the TME. 15,983 single cells from the two conditions were sequenced and clustered into six transcriptionally distinct groups. g, UMAP clustering of all the PMEL CD8+ TILs. h, Indicated co-inhibitory gene marker expression on the UMAP. i, Comparison of cell proportion in each cluster. j, Comparison of functional gene expression in the terminally exhausted-like T cells. Image credit: Feng B., et al. Nature 2024(CC BY.4.0) 

Single cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma (Rade M., et al., Nat. Cancer, 2024): 

Multiple myeloma is a complex and incurable blood cancer that affects plasma cells in the bone marrow, leading to weakened immunity, bone damage, and other serious complications. Research into this disease is crucial to develop more effective therapies, overcome treatment resistance, and improve quality of life and survival rates of those affected.  

A German research group identified key markers of resistance and relapse in CAR T cell therapy for relapsed/refractory multiple myeloma using single cell multi-omic analysis of blood and bone marrow samples. Using a set of customized 61 oligonucleotide-bound antibodies, they were able to perform single cell surface proteomics (CITE-seq).

Nonresponders showed an immunosuppressive microenvironment with increased CD39+ monocytes and reduced CD8+ T cell and natural killer cell function. Hyperexpanded CAR T cell clones exhibited cytotoxic and exhausted phenotypes, while low/intermediate expanded clones were less affected. The study highlights potential targets, such as PD1, to enhance CAR T cell functionality and durability, suggesting that resistance is driven by an immunosuppressive microenvironment. 

IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases (Zhao Y., et al., Nat. Biotech, 2024): 

A recent study published by Swiss scientists demonstrates a breakthrough in improving CAR T cell therapy for solid tumors by engineering the cells to secrete interleukin-10 (IL-10). Single cell RNA sequencing revealed IL-10 CAR T cells preserved mitochondrial health, enhanced oxidative phosphorylation, and boosted proliferation and effector function, leading to complete tumor regression in multiple cancer models. Additionally, these cells induced durable, stem cell-like memory responses, offering long-term protection against tumor rechallenge. This metabolic armoring approach provides a promising, generalizable strategy to overcome CAR T cell dysfunction in solid tumors. 

RAIN: machine learning-based identification for HIV-1 bNAbs (Foglierini M., et al., Nat. Commun., 2024): 

Is machine-learning part of the innovations that will shape the future of medical healthcare?

Yes, we do believe that our path towards precision medicine 2.0 will lie in the synergistic usage of cutting-edge research and computational power such as artificial intelligence and machine learning. 

The RAIN pipeline, published by Swiss researchers in Nature Communications, combines single-cell B-cell receptor (BCR) sequencing with machine learning to identify broadly neutralizing antibodies (bNAbs) against HIV-1. By analyzing full-length variable heavy and light-chain sequences, RAIN uses five key amino acid sequence characteristics to distinguish bNAbs from other antibodies. The study’s results highlight the importance of unconventional mutations in BCR frameworks, linked to antibody maturation and enhanced binding affinity. This approach offers a powerful tool for antibody discovery, with applications in immune-related diseases and vaccine development. 

 

These groundbreaking studies highlight the immense potential of single cell technologies to unravel complex biological systems and drive innovation particularly in the field of immuno-oncology. As research continues to evolve, single cell approaches will undoubtedly remain at the forefront of transformative scientific discoveries. 

 Read all our 2024 publications and more from the archive, here.

References:

Feng, B., Bai, Z., Zhou, X. et al. The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 634, 712–720 (2024). https://doi.org/10.1038/s41586-024-07962-4 

Rade, M., Grieb, N., Weiss, R. et al. Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma. Nat Cancer 5, 1318–1333 (2024). https://doi.org/10.1038/s43018-024-00763-8 

Zhao, Y., Chen, J., Andreatta, M. et al. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases. Nat Biotechnol 42, 1693–1704 (2024). https://doi.org/10.1038/s41587-023-02060-8 

Foglierini, M., Nortier, P., Schelling, R. et al. RAIN: machine learning-based identification for HIV-1 bNAbs. Nat Commun 15, 5339 (2024). https://doi.org/10.1038/s41467-024-49676-1 

 

A post by Elena Pleqi

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