Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

CAR-T therapies have shown remarkable success in treating hematological malignancies. However, effectiveness against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), such as TGF-β signaling and upregulated immune checkpoints (ICs). Furthermore, identifying universal, tumor-specific targets for CAR-T cells in solid tumors is challenging, but using reinvigorated, immunosuppressive-resistant tumor-infiltrating lymphocytes (TILs) could be a promising alternative approach. Unlike nucleases, which may induce genotoxic DNA double-strand breaks, multiplexed Zinc Finger Repressors (ZFR) offer a safer alternative for knocking out TME-related immunosuppressive factors. We epigenetically repressed PD-1 expression both in CAR-T cells and TILs from colorectal liver metastases. PD-1 repression did not affect T cell viability, proliferation, or functionality. In a murine B cell lymphoma model, PD-1-repressed CD19-CAR-T cells exhibited enhanced anti-tumor activity and improved survival. Notably, PD-1 repression alone did not increase cytotoxicity against a PD-L1-positive colorectal cell line in vitro. To further increase anti-tumor potency in this context, ZFR-expressing lentiviral vectors targeting PD-1 and other ICs (LAG-3, TIM-3, TIGIT) or TGFBR2 were developed, improving significantly the cytotoxic activity in TILs. This strategy highlights the potential to enhance tumor-reactive T cells and improve anti-cancer immunotherapies by epigenetically repressing immunosuppressive factors in the TME using multiplexed ZFRs.

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Synthetic Gene Circuits as a Promising Approach in Cancer Immunotherapy

Ananthakumar,

Nanjundeshwara,

Lakshmaiah

et al. 2024

Advances in Medical Diagnosis, Treatment, and Care

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Cancer immunotherapy has emerged as a revolutionary approach in the fight against cancer. Unlike traditional treatments like chemotherapy and radiation, immunotherapy harnesses the power of the body's own immune system to identify and destroy cancer cells. Cancer immunotherapy has emerged as a promising therapy, but limitations in specificity and control hinder its full potential. Synthetic gene circuits offer a revolutionary approach to address these challenges. This chapter emphasizes the diverse applications of synthetic gene circuits in cancer immunotherapy. Additionally, the authors discuss the advantages and limitations of AND gate circuits for minimizing off-target effects, engineered bacteria for targeted tumour manipulation, and T-cell engineering for enhanced anti-tumour activity. Ultimately, traditional therapies and synthetic gene circuits are not mutually exclusive. While traditional therapies offer proven effectiveness and accessibility, synthetic gene circuits hold immense promise for personalized, long-term solutions.

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Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

Cited by 3 publications

References 231 publications

The physiological and pathological roles of RNA modifications in T cells

The physiological and pathological roles of RNA modifications in T cells

Enhanced anti-tumor activity by Zinc Finger Repressor-driven epigenetic silencing of immune checkpoints and TGFBR2 in CAR-T cells and TILs

Synthetic Gene Circuits as a Promising Approach in Cancer Immunotherapy

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