Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity

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Abstract

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8 + tumor-infiltrating lymphocytes (TILs), the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life–extended interleukin (IL)-10/Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8 + TILs by promoting oxidative phosphorylation (OXPHOS), a process independent of the progenitor exhausted T cells. IL-10/Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in a majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent OXPHOS can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

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Elements of cancer immunity and the cancer–immune set point

Daniel Chen, Ira Mellman (2017)

Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is

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Padmanee Sharma, Siwen Hu-Lieskovan, Jennifer A. Wargo … (2017)

Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

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Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9

John Doench, Nicolò Fusi, Meagan Sullender … (2016)

CRISPR-Cas9-based genetic screens are a powerful new tool in biology. By simply altering the sequence of the single-guide RNA (sgRNA), Cas9 can be reprogrammed to target different sites in the genome with relative ease, but the on-target activity and off-target effects of individual sgRNAs can vary widely. Here, we use recently-devised sgRNA design rules to create human and mouse genome-wide libraries, perform positive and negative selection screens and observe that the use of these rules produced improved results. Additionally, we profile the off-target activity of thousands of sgRNAs and develop a metric to predict off-target sites. We incorporate these findings from large-scale, empirical data to improve our computational design rules and create optimized sgRNA libraries that maximize on-target activity and minimize off-target effects to enable more effective and efficient genetic screens and genome engineering.