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A T-cell resilience model associated with response to immunotherapy in multiple tumor types

ABSTRACT: Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (Tumor-resilient T cell, https://resilience.ccr.cancer.gov), a computational model and web server that utilizes single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as TGFβ, TRAIL, and PGE2. Analyzing T-cell transcriptomic data from 72 pretreatment and 84 pre-manufacture patient samples, Tres reliably predicts the clinical effectiveness of immune checkpoint blockade or adoptive cell transfer in melanoma, lung, and B-cell malignancies. Further, Tres identified FIBP, whose functions are largely unknown without previous links to T cells, as the top negative marker of tumor-resilient T cells across many cancers. FIBP knockouts in murine and human CD8+ T cells significantly enhanced T-cell mediated cancer-killing in invitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in-vivo efficacy of adoptive cell transfer by limiting cholesterol metabolism, which otherwise inhibits effector T-cell function. These results demonstrate Tres’s utility in identifying clinical biomarkers of T-cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE186428 | GEO | 2022/03/05

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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A T-cell resilience model associated with response to immunotherapy in multiple tumor types

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