title: Resistance of cancers to immunologic cytotoxicity and adoptive immunotherapy via X-linked inhibitor of apoptosis protein expression and coexisting defects in mitochondrial death signaling.
abstract: The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-gamma, and Apo2 ligand/tumor necrosis factor-related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell-mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-x(L), or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-gamma/Apo2L/TRAIL- or granzyme B-induced apoptosis, lymphocyte-mediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Ravi
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: Ajay
authors.initials: A
authors.lastname: Jain
authors.forename: Vui
authors.initials: V
authors.lastname: Pham
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Traci
authors.initials: T
authors.lastname: Prouser
authors.forename: Sanju
authors.initials: S
authors.lastname: Jalla
authors.forename: Xianzheng
authors.initials: X
authors.lastname: Zhou
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Atul
authors.initials: A
authors.lastname: Bedi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D005260:Female; D053804:Granzymes; D045325:HCT116 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000201:enzymology / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D020169:Caspases