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A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.

ABSTRACT: T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants. SIGNIFICANCE: This study demonstrates the first report of in vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse.This article is highlighted in the In This Issue feature, p. 521.

SUBMITTER: Upadhyay R

PROVIDER: S-EPMC7933082 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.

Upadhyay Ranjan R Boiarsky Jonathan A JA Pantsulaia Gvantsa G Svensson-Arvelund Judit J Lin Matthew J MJ Wroblewska Aleksandra A Bhalla Sherry S Scholler Nathalie N Bot Adrian A Rossi John M JM Sadek Norah N Parekh Samir S Lagana Alessandro A Baccarini Alessia A Merad Miriam M Brown Brian D BD Brody Joshua D JD

Cancer discovery 20201217 3

T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytot ...[more]

PMID: 33334730

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) are emerging promising agents for the treatment of patients with esophageal squamous cell carcinoma (ESCC), however, there are only a small proportion respond to ICI therapy. Therefore, selecting candidate patients who will benefit the most from these drugs is critical. However, validated biomarkers for predicting immunotherapy response and overall survival are lacking. As the fundamental principle of ICI therapy is T cell-mediated tumor killing (TTK), we aimed to develop a unique TTK-related gene prognostic index (TTKPI) for predicting survival outcomes and responses to immune-based therapy in ESCC patients.MethodsTranscriptomic and clinical information of ESCC patients were from the GSE53625, GSE53624, GSE47404 and TCGA datasets. TTK-related genes were from the TISIDB database. The LASSO Cox regression model was employed to create the TTKPI. The prediction potential of the TTKPI was evaluated using the KM curve and time-dependent ROC curve analysis. Finally, the relationship between TTKPI and immunotherapy efficacy was investigated in clinical trials of ICIs (GSE91061, GSE135222, IMvigor210 cohort). The role of KIF11 in accelerating tumor progression was validated via a variety of functional experiments, including western blot, CCK-8, colony formation, wound healing scratch, and xenograft tumor model. The KIF11 expression was detected by multiplex fluorescent immunohistochemistry on tissue microarray from ESCC patients.ResultsWe constructed the TTKPI based on 8 TTK-related genes. The TTKPI low-risk patients exhibited better overall survival. TTKPI was significantly and positively correlated with the main immune checkpoint molecules levels. Furthermore, the low-risk patients were more prone to reap the benefits of immunotherapy in the cohort undergoing anti-PD-L1 therapy. Moreover, we performed functional experiments on KIF11, which ranked as the most significant prognostic risk gene among the 8 TTK-related genes. Our findings identified that KIF11 knockdown significantly hindered cell proliferation and mobility in ESCC cells. The KIF11 expression was negatively related with CD8+ T cell infiltration in ESCC patient samples.ConclusionsThe TTKPI is a promising biomarker for accurately determining survival and predicting the effectiveness of immunotherapy in ESCC patients. This risk indicator can help patients receive timely and precise early intervention, thereby advancing personalized medicine and facilitating precise immuno-oncology research. KIF11 plays a crucial role in driving tumor proliferation and migration and may act as a potential tumor biomarker of ESCC.

Dataset Information

A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.

Publications

A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.

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