https://escholarship.org/content/qt16g5z0rz/qt16g5z0rz.pdf?t=qtpltt

Engineering CAR-T Cells for Next-Generation Cancer Therapy

Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4+ macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3+ T cells with high proportion of TIGIT+ cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.

/pdf/single-cell-rna-landscape-of-intratumoral-heterogeneity-and-39ix46xbla.pdf

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.

https://www.onlinelibrary.wiley.com/doi/epdf/10.1111/cei.13407

TIGIT as an emerging immune checkpoint

Chimeric antigen receptor T cell (CAR-T) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin's lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we employed single cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and post-infusion into NHL patients. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate TIGIT blockade alone improves the anti-tumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in NHL patients.

Sequential single cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-Hodgkin's lymphoma.

Cancer immunotherapy is fast becoming one of the most promising means of treating malignant disease. Cancer vaccines, adoptive cell transfer therapies, and immune checkpoint blockade have all shown varying levels of success in the clinical management of several cancer types in recent years. However, despite the clinical benefits often achieved by these regimens, an ongoing problem for many patients is the inherent or acquired resistance of their cancer to immunotherapy. It is now appreciated that dendritic cells and T lymphocytes both play key roles in antitumor immune responses and that the tumor microenvironment presents a number of barriers to the function of these cells that can ultimately limit the success of immunotherapy. In particular, the engagement of several immunologic and metabolic checkpoints within the hostile tumor microenvironment can severely compromise the antitumor functions of these important immune populations. This review highlights work from both preclinical and clinical studies that has shaped our understanding of the tumor microenvironment and its influence on dendritic cell and T cell function. It focuses on clinically relevant targeted and immunotherapeutic strategies that have emerged from these studies in an effort to prevent or overcome immune subversion within the tumor microenvironment. Emphasis is also placed on the potential of next-generation combinatorial regimens that target metabolic and immunologic impediments to dendritic cell and T lymphocyte function as strategies to improve antitumor immune reactivity and the clinical outcome of cancer immunotherapy going forward.

Tumor microenvironmental influences on dendritic cell and T cell function: A focus on clinically relevant immunologic and metabolic checkpoints.

Tumors can employ different mechanisms to evade immune surveillance and function. Overexpression of co-inhibitory ligands that bind to checkpoint molecules on the surface of T-cells can greatly impair the function of latter. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is such a co-inhibitory receptor expressed by T and NK cells which, upon binding to its ligand (e.g., CD155), can diminish cytokine production and effector function. Additionally, the absence of positive co-stimulation at the tumor site can further dampen T-cell response. As T-cell genetic engineering has become clinically-relevant in the recent years, we devised herein a strategy aimed at enhancing T-cell anti-tumor function by diverting T-cell coinhibitory signals into positive ones using a chimeric costimulatory switch receptor (CSR) composed of the TIGIT exodomain fused to the signaling domain of CD28. After selecting an optimized TIGIT-28 CSR, we co-transduced it along with tumor-specific TCR or CAR into human T-cells. TIGIT-28-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor cells. TIGIT-28 enhancing capability was also demonstrated in an original in vitro model of T-cell of hypofunction induction upon repetitive antigen exposure. Finally, we tested the function of this molecule in the context of a xenograft model of established human melanoma tumors and showed that TIGIT-28-engineered human T-cells demonstrated superior anti-tumor function. Overall, we propose that TIGIT-based CSR can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.

/pdf/a-tigit-based-chimeric-co-stimulatory-switch-receptor-3k65zdf6ya.pdf

A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function.

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A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function.