Browsing by Subject "ANTITUMOR IMMUNITY"

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  • Zafar, Sadia; Sorsa, Suvi; Siurala, Mikko; Hemminki, Otto; Havunen, Riikka; Cervera-Carrascon, Victor; Santos, Joao Manuel; Wang, Hongjie; Lieber, Andre; De Gruijl, Tanja; Kanerva, Anna; Hemminki, Akseli (2018)
    Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach in cancer immunotherapy. One of the major obstacles in cancer immunotherapy in general is the immunosuppressive tumor microenvironment, which hampers the maturation and activation of DCs. Therefore, human clinical outcomes with DC therapy alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing human CD40L, to modulate the tumor microenvironment with subsequently improved function of DCs. We evaluated the synergistic effects of Ad3-hTERT-CMV-hCD40L and DCs in the presence of human peripheral blood mononuclear cells ex vivo and in vivo. Tumors treated with Ad3-hTERT-CMV-hCD40L and DCs featured greater antitumor effect compared with unarmed virus or either treatment alone. 100% of humanized mice survived to the end of the experiment, while mice in all other groups died by day 88. Moreover, adenovirally-delivered CD40L induced activation of DCs, leading to induction of Th1 immune responses. These results support clinical trials with Ad3-hTERT-CMV-hCD40L in patients receiving DC therapy.
  • Galluzzi, Lorenzo; Vitale, Ilio; Warren, Sarah; Adjemian, Sandy; Agostinis, Patrizia; Martinez, Aitziber Buqué; Chan, Timothy A; Coukos, George; Demaria, Sandra; Deutsch, Eric; Draganov, Dobrin; Edelson, Richard L; Formenti, Silvia C; Fucikova, Jitka; Gabriele, Lucia; Gaipl, Udo S; Gameiro, Sofia R; Garg, Abhishek D; Golden, Encouse; Han, Jian; Harrington, Kevin J; Hemminki, Akseli; Hodge, James W; Hossain, Dewan Md Sakib; Illidge, Tim; Karin, Michael; Kaufman, Howard L; Kepp, Oliver; Kroemer, Guido; Lasarte, Juan Jose; Loi, Sherene; Lotze, Michael T; Manic, Gwenola; Merghoub, Taha; Melcher, Alan A; Mossman, Karen L; Prosper, Felipe; Rekdal, Øystein; Rescigno, Maria; Riganti, Chiara; Sistigu, Antonella; Smyth, Mark J; Spisek, Radek; Stagg, John; Strauss, Bryan E; Tang, Daolin; Tatsuno, Kazuki; van Gool, Stefaan W; Vandenabeele, Peter; Yamazaki, Takahiro; Zamarin, Dmitriy; Zitvogel, Laurence; Cesano, Alessandra; Marincola, Francesco M (2020)
    Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
  • Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B.; Behrens, Sabine; Goode, Ellen L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Easton, Douglas F.; Wang, Qin; Benitez, Javier; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Fasching, Peter A.; Haeberle, Lothar; Peto, Julian; dos-Santos-Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guenel, Pascal; Truong, Therese; Bojesen, Stig E.; Flyger, Henrik; Nielsen, Sune F.; Nordestgaard, Borge G.; Gonzalez-Neira, Anna; Menendez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Doerk, Thilo; Bogdanova, Natalia V.; Mannermaa, Arto; Hartikainen, Jaana M.; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J.; Hallberg, Emily; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S.; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L.; Glendon, Gord; Garcia-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S.; Pharoah, Paul D. P.; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B.; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny (2016)
    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A > G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 x 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 x 10(-3) and 7.0 x 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 x 10(-3), 4.5 x 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
  • Ylösmäki, Erkko; Malorzo, Cristina; Capasso, Cristian; Honkasalo, Oona; Fusciello, Manlio; Martins, Beatriz; Ylösmäki, Leena; Louna, Antti; Feola, Sara; Paavilainen, Henrik; Peltonen, Karita; Hukkanen, Veijo; Viitala, Tapani; Cerullo, Vincenzo (2018)
    The approval of the first oncolytic virus for the treatment of metastatic melanoma and the compiling evidence that the use of oncolytic viruses can enhance cancer immunotherapies targeted against various immune checkpoint proteins has attracted great interest in the field of cancer virotherapy. We have developed a novel platform for clinically relevant enveloped viruses that can direct the virus-induced immune response against tumor antigens. By physically attaching tumor- specific peptides onto the viral envelope of vaccinia virus and herpes simplex virus 1 (HSV-1), we were able to induce a strong T cell-specific immune response toward these tumor antigens. These therapeutic peptides could be attached onto the viral envelope by using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat N-terminally fused to the tumor-specific peptides or, alternatively, therapeutic peptides could be conjugated with cholesterol for the attachment of the peptides onto the viral envelope. We used two mouse models of melanoma termed B16. OVA and B16-F10 for testing the efficacy of OVA SIINFEKL-peptide-coated viruses and gp100-Trp2-peptide-coated viruses, respectively, and show that by coating the viral envelope with therapeutic peptides, the anti-tumor immunity and the number of tumor-specific CD8(+) T cells in the tumor microenvironment can be significantly enhanced.
  • Schönefeldt, Susann; Wais, Tamara; Herling, Marco; Mustjoki, Satu; Bekiaris, Vasileios; Moriggl, Richard; Neubauer, Heidi A. (2021)
    Simple Summary:& nbsp;gamma delta T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, gamma delta T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of gamma delta T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of gamma delta T-cell transformation, summarising the resulting gamma delta T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.& nbsp;gamma delta T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional alpha beta T cells, gamma delta T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. gamma delta T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-gamma or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, gamma delta T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of gamma delta T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of gamma delta T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of gamma delta T-cell transformation, summarising the main gamma delta T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.