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 3

ColVI in the UPS TME promotes CD8+ T cell dysfunction.

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ColVI in the UPS TME promotes CD8+ T cell dysfunction. (A) Representativ...
(A) Representative wide-field images of ColVI immunofluorescence in dECMs generated from control and shCol6a1-expressing B6-KP cells. Scale bars: 20 μm. Brightness and contrast were adjusted for publication. (B and C) Representative contour plots (B) and quantification (C) of Pd1 and Tim-3 coexpression in CD44+CD8+ T cells incubated on dECM derived from control or shCol6a1 KP cells. (D) Average longitudinal cytolysis of shScr- or shCOL6A1-expressing human STS-109 UPS cells cocultured with CART-TnMUC1 cells from 3 independent human donors (n = 2 for shCOL6A1 #1). Points for individual replicates overlap. Measurements indicate percent target cell (UPS cell) cytolysis. (E) Quantification of area under the curve from D; 1-way ANOVA with Dunnett’s test (vs. shScr) for each ratio. In D and E, shScr data are identical to those in Figure 1J (performed in the same experiment). (F) Tumor growth curves from subcutaneous (flank) syngeneic transplant of 3 × 104 B6-KP cells in Matrigel expressing control or Col6a1-targeting shRNAs in syngeneic C57BL/6 mice; 2-way ANOVA. (G) Individual tumors from F. (H) Tumor growth curves depicting subcutaneous (flank) syngeneic transplant of 5 × 105 KP cells (SKPY42.1 cell line) expressing control or Col6a1-targeting shRNAs in C57BL/6 mice treated with α-CD8α every 3 days. (I) Tumor growth curves depicting syngeneic orthotopic transplant (into the gastrocnemius muscle) of 2.5 × 105 KP cells (SKPY42.1 cell line) expressing control or Col6a1-targeting shRNAs in C57BL/6 mice; 2-way repeated-measures ANOVA, SEM. (J and K) Representative contour plots (J) and quantification (K) of T cell dysfunction markers in CD8+ T cells from control and shCol6a1 orthotopic tumors from I. Each point in K represents an individual tumor. Two-tailed unpaired t tests.