Secreted Gelsolin Inhibits DNGR-1-dependent Cross-presentation and Cancer Immunity

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Jun 3

PMID 34081922

Citations 47

Authors

Evangelos Giampazolias

Oliver Schulz

Kok Haw Jonathan Lim

Neil C Rogers

Probir Chakravarty

Naren Srinivasan

Oliver Gordon

Ana Cardoso

Michael D Buck

Enzo Z Poirier

Johnathan Canton

Santiago Zelenay

Stefano Sammicheli

Natalia Moncaut

Sunita Varsani-Brown

Ian Rosewell

Caetano Reis e Sousa

Affiliations

Soon will be listed here.

Abstract

Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8 T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8 T cell responses.

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References

Lees A, Haddad J, Lin S . Brevin and vitamin D binding protein: comparison of the effects of two serum proteins on actin assembly and disassembly. Biochemistry. 1984; 23(13):3038-47. DOI: 10.1021/bi00308a030. View

Barry K, Hsu J, Broz M, Cueto F, Binnewies M, Combes A . A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med. 2018; 24(8):1178-1191. PMC: 6475503. DOI: 10.1038/s41591-018-0085-8. View

Matsushita H, Vesely M, Koboldt D, Rickert C, Uppaluri R, Magrini V . Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012; 482(7385):400-4. PMC: 3874809. DOI: 10.1038/nature10755. View

Faustino-Rocha A, Oliveira P, Pinho-Oliveira J, Teixeira-Guedes C, Soares-Maia R, DA Costa R . Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Lab Anim (NY). 2013; 42(6):217-24. DOI: 10.1038/laban.254. View

Alloatti A, Rookhuizen D, Joannas L, Carpier J, Iborra S, Magalhaes J . Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity. J Exp Med. 2017; 214(8):2231-2241. PMC: 5551575. DOI: 10.1084/jem.20170229. View

Kozik P, Gros M, Itzhak D, Joannas L, Heurtebise-Chretien S, Krawczyk P . Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity. Cell Rep. 2020; 32(2):107905. PMC: 7370168. DOI: 10.1016/j.celrep.2020.107905. View

Vasconcellos C, Lind S . Coordinated inhibition of actin-induced platelet aggregation by plasma gelsolin and vitamin D-binding protein. Blood. 1993; 82(12):3648-57. View

Asano K, Nabeyama A, Miyake Y, Qiu C, Kurita A, Tomura M . CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011; 34(1):85-95. DOI: 10.1016/j.immuni.2010.12.011. View

Carlier M, Ressad F, Pantaloni D . Control of actin dynamics in cell motility. Role of ADF/cofilin. J Biol Chem. 1999; 274(48):33827-30. DOI: 10.1074/jbc.274.48.33827. View

10.

Kwiatkowski D . Functions of gelsolin: motility, signaling, apoptosis, cancer. Curr Opin Cell Biol. 1999; 11(1):103-8. DOI: 10.1016/s0955-0674(99)80012-x. View

11.

Spranger S, Dai D, Horton B, Gajewski T . Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017; 31(5):711-723.e4. PMC: 5650691. DOI: 10.1016/j.ccell.2017.04.003. View

12.

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

13.

Zorn E, Hercend T . A natural cytotoxic T cell response in a spontaneously regressing human melanoma targets a neoantigen resulting from a somatic point mutation. Eur J Immunol. 1999; 29(2):592-601. DOI: 10.1002/(SICI)1521-4141(199902)29:02<592::AID-IMMU592>3.0.CO;2-2. View

14.

Wculek S, Cueto F, Mujal A, Melero I, Krummel M, Sancho D . Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2019; 20(1):7-24. DOI: 10.1038/s41577-019-0210-z. View

15.

Cantu C, Bose F, Bianchi P, Reali E, Colzani M, Cantu I . Defective erythroid maturation in gelsolin mutant mice. Haematologica. 2012; 97(7):980-8. PMC: 3396666. DOI: 10.3324/haematol.2011.052522. View

16.

Schulz O, Reis e Sousa C . Cross-presentation of cell-associated antigens by CD8alpha+ dendritic cells is attributable to their ability to internalize dead cells. Immunology. 2002; 107(2):183-9. PMC: 1782783. DOI: 10.1046/j.1365-2567.2002.01513.x. View

17.

Yatim N, Cullen S, Albert M . Dying cells actively regulate adaptive immune responses. Nat Rev Immunol. 2017; 17(4):262-275. DOI: 10.1038/nri.2017.9. View

18.

Kwiatkowski D, Mehl R, Yin H . Genomic organization and biosynthesis of secreted and cytoplasmic forms of gelsolin. J Cell Biol. 1988; 106(2):375-84. PMC: 2114988. DOI: 10.1083/jcb.106.2.375. View

19.

Haddad J, Hu Y, Kowalski M, Laramore C, Ray K, Robzyk P . Identification of the sterol- and actin-binding domains of plasma vitamin D binding protein (Gc-globulin). Biochemistry. 1992; 31(31):7174-81. DOI: 10.1021/bi00146a021. View

20.

Roberts E, Broz M, Binnewies M, Headley M, Nelson A, Wolf D . Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell. 2016; 30(2):324-336. PMC: 5374862. DOI: 10.1016/j.ccell.2016.06.003. View