American Association for Cancer Research
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Figure S1 from HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion

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posted on 2023-10-13, 07:41 authored by Andrew Nguyen, Dominique Brown, Ramya Krishnan, Donald Bastin, Li Deng, Lan Chen, Omar Salem, Scott R. Walsh, Jonathan L. Bramson, Yonghong Wan

Figure S1: Transferred T-cell proliferation and cell death over time

Funding

Canadian Institutes of Health Research (IRSC)

Canadian Cancer Society (CCS)

Terry Fox Research Institute (TFRI)

Ontario Institute for Cancer Research (OICR)

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ARTICLE ABSTRACT

T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden–related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2–STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell–like CD44+ Tim-3hi TCF1− CD127− KLRG1+ differentiation. Tumor burden–induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.

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