Browsing by MeSH term "Tumor Escape"
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Publication An unexpected role for PD-L1 in front-rear polarization and directional migration.(Rockefeller University Press, 2022-05-02) Sánchez-Álvarez, Miguel; del Pozo, Miguel AngelProgrammed cell death-ligand 1 (PD-L1)-mediated T cell inhibition through PD-1 is a key checkpoint frequently exploited by tumors to evade immunity. In this issue, Wang et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202108083) reveal an unexpected role for PD-L1 in promoting tumor cell front-rear polarity and directionally persistent cell migration, independently of PD-1.Publication DNGR-1 limits Flt3L-mediated antitumor immunity by restraining tumor-infiltrating type I conventional dendritic cells.(BMJ Publishing Group, 2021-05) Cueto, Francisco J; Del Fresno, Carlos; Brandi, Paola; Combes, Alexis J; Hernández-García, Elena; Sánchez-Paulete, Alfonso R; Enamorado, Michel; Bromley, Christian P; Gomez, Manuel J; Conde-Garrosa, Ruth; Mañes, Santos; Zelenay, Santiago; Melero, Ignacio; Iborra, Salvador; Krummel, Matthew F; Sancho, David; Fundación La Caixa; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; NIHR - Manchester Biomedical Research Centre (Reino Unido); Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Fondation ACTERIA (Acting on European Research in Immunology and Allergology); Atresmedia; Fundación La Marató TV3; Fundación ProCNIC; Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.Publication The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.(BMJ Publishing Group, 2024-08-08) López-Gil, Juan Carlos; García-Silva, Susana; Ruiz-Cañas, Laura; Navarro, Diego; Palencia-Campos, Adrián; Giráldez-Trujillo, Antonio; Earl, Julie; Dorado, Jorge; Gómez-López, Gonzalo; Monfort-Vengut, Ana; Alcalá, Sonia; Gaida, Matthias M; García-Mulero, Sandra; Cabezas-Sáinz, Pablo; Batres-Ramos, Sandra; Barreto, Emma; Sánchez-Tomero, Patricia; Vallespinós, Mireia; Ambler, Leah; Lin, Meng-Lay; Aicher, Alexandra; García García de Paredes, Ana; de la Pinta, Carolina; Sanjuanbenito, Alfonso; Ruz-Caracuel, Ignacio; Rodríguez-Garrote, Mercedes; Guerra, Carmen; Carrato, Alfredo; de Cárcer, Guillermo; Sánchez, Laura; Nombela-Arrieta, César; Espinet, Elisa; Sanchez-Arevalo Lobo, Víctor Javier; Heeschen, Christopher; Sainz, Bruno; Fundación La Caixa; EMBO Scientific Exchange Fellowship; Juan de la Cierva Formacion; Fero Foundation Grant; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Xunta de Galicia (España); University of Zurich; German Research Foundation (DFG); Unión Europea. Comisión Europea. European Research Council (ERC); Fondazione AIRC per la ricerca sul cancro; Shanghai Municipal Education Commission (SHMEC); National Natural Science Foundation of China (NSFC)OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNF?)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.