Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment
Ashley M. Fuller, Hawley C. Pruitt, Ying Liu, Valerie M. Irizarry-Negron, Hehai Pan, Hoogeun Song, Ann DeVine, Rohan S. Katti, Samir Devalaraja, Gabrielle E. Ciotti, Michael V. Gonzalez, Erik F. Williams, Ileana Murazzi, Dimitris Ntekoumes, Nicolas Skuli, Hakon Hakonarson, Daniel J. Zabransky, Jose G. Trevino, Ashani Weeraratna, Kristy Weber, Malay Haldar, Joseph A. Fraietta, Sharon Gerecht, T.S. Karin Eisinger-Mathason
Ashley M. Fuller, Hawley C. Pruitt, Ying Liu, Valerie M. Irizarry-Negron, Hehai Pan, Hoogeun Song, Ann DeVine, Rohan S. Katti, Samir Devalaraja, Gabrielle E. Ciotti, Michael V. Gonzalez, Erik F. Williams, Ileana Murazzi, Dimitris Ntekoumes, Nicolas Skuli, Hakon Hakonarson, Daniel J. Zabransky, Jose G. Trevino, Ashani Weeraratna, Kristy Weber, Malay Haldar, Joseph A. Fraietta, Sharon Gerecht, T.S. Karin Eisinger-Mathason
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Research Article Oncology

Oncogene-induced matrix reorganization controls CD8+ T cell function in the soft-tissue sarcoma microenvironment

Abstract

CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.

Authors

Ashley M. Fuller, Hawley C. Pruitt, Ying Liu, Valerie M. Irizarry-Negron, Hehai Pan, Hoogeun Song, Ann DeVine, Rohan S. Katti, Samir Devalaraja, Gabrielle E. Ciotti, Michael V. Gonzalez, Erik F. Williams, Ileana Murazzi, Dimitris Ntekoumes, Nicolas Skuli, Hakon Hakonarson, Daniel J. Zabransky, Jose G. Trevino, Ashani Weeraratna, Kristy Weber, Malay Haldar, Joseph A. Fraietta, Sharon Gerecht, T.S. Karin Eisinger-Mathason

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Figure 1

YAP1+ UPS cells inhibit CD8+ T cell activation and promote dysfunction.

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YAP1+ UPS cells inhibit CD8+ T cell activation and promote dysfunction. ...
(A) Kaplan-Meier latency curves of KP and KPY UPS tumors (n > 10 per genotype). (B) Validation of genotypes from A (fl, floxed; wt, wild type). The Trp53fl and Yap1fl bands and their respective ladders are from the same gels but were separated for presentation. (C) Metascape pathway analysis of 5 unique bulk KP and KPY tumors. Includes all genes with greater than 2-fold expression increase in KPY versus KP, identified via microarrays. (D and E) Representative contour plots (D) and quantification (E) of CD8+CD44hi and CD4+CD44hi T cells in KP and KPY tumors. (F and G) Representative contour plots (F) and quantification (G) of CD39, Tim-3, and Pd1 expression in CD8+ T cells from KP and KPY tumors. For E and G, points represent individual tumors; 2-tailed unpaired t tests. (H) Gzmb quantitative reverse transcriptase PCR (qRT-PCR) in bulk KP and KPY tumors; 2-tailed unpaired t test. (I) Kaplan-Meier survival curves of KP and KPY mice treated with α-Pd1 or control. Red and black circles in control curves indicate IgG-injected and uninjected mice, respectively. Open circle, mouse with durable tumor regression; x axis, days to maximum volume since adeno Cre injection. (J) Average longitudinal cytolysis of shScr or shYAP1 human STS-109 UPS cells during coculture with CART-TnMUC1 cells from 3 independent human donors. Measurements indicate percent target (UPS) cell cytolysis. Quantification: 1-way ANOVA with Dunnett’s test (vs. shScr) for each ratio. Points for individual replicates overlap. shScr data are identical to those in Figure 3, D and E (performed in the same experiment). (K and L) Kaplan-Meier survival curves of UPS patients in TCGA-SARC stratified by intratumoral GZMB (K) and PRF1 (L) expression. (M) Correlation of YAP1 with GZMB and PRF1 gene expression in UPS tumors from TCGA-SARC.