RT Journal Article
SR Electronic
T1 Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000233
DO 10.1136/jitc-2019-000233
VO 8
IS 1
A1 Nicolas Torres
A1 María Victoria Regge
A1 Florencia Secchiari
A1 Adrián David Friedrich
A1 Raúl Germán Spallanzani
A1 Ximena Lucía Raffo Iraolagoitia
A1 Sol Yanel Núñez
A1 Jessica Mariel Sierra
A1 Andrea Ziblat
A1 María Cecilia Santilli
A1 Nicolás Gilio
A1 Evangelina Almada
A1 Constanza Lauche
A1 Romina Pardo
A1 Carolina Inés Domaica
A1 Mercedes Beatriz Fuertes
A1 Kevin Patrick Madauss
A1 Kenneth W Hance
A1 Israel S Gloger
A1 Vanesa Zylberman
A1 Fernando Alberto Goldbaum
A1 Norberto Walter Zwirner
YR 2020
UL http://jitc.bmj.com/content/8/1/e000233.abstract
AB Background Natural killer and cytotoxic CD8+ T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I chain-related proteins A and B (MICA and MICB). Both molecules are overexpressed on a great variety of tumors from different tissues, making them attractive targets for immunotherapy. However, tumors shed MICA and MICB, and the soluble forms of both (sMICA and sMICB) mediate tumor-immune escape. Some reports indicate that anti-MICA antibodies (Ab) can promote the restoration of antitumor immunity through the induction of direct antitumor effects (antibody-dependent cell-mediated cytotoxicity, ADCC) and scavenging of sMICA. Therefore, we reasoned that an active induction of anti-MICA Ab with an immunogenic protein might represent a novel therapeutic and prophylactic alternative to restore antitumor immunity.Methods We generated a highly immunogenic chimeric protein (BLS-MICA) consisting of human MICA fused to the lumazine synthase from Brucella spp (BLS) and used it to generate anti-MICA polyclonal Ab (pAb) and to investigate if these anti-MICA Ab can reinstate antitumor immunity in mice using two different mouse tumors engineered to express MICA. We also explored the underlying mechanisms of this expected therapeutic effect.Results Immunization with BLS-MICA and administration of anti-MICA pAb elicited by BLS-MICA significantly delayed the growth of MICA-expressing mouse tumors but not of control tumors. The therapeutic effect of immunization with BLS-MICA included scavenging of sMICA and the anti-MICA Ab-mediated ADCC, promoting heightened intratumoral M1/proinflammatory macrophage and antigen-experienced CD8+ T cell recruitment.Conclusions Immunization with the chimeric protein BLS-MICA constitutes a useful way to actively induce therapeutic anti-MICA pAb that resulted in a reprogramming of the antitumor immune response towards an antitumoral/proinflammatory phenotype. Hence, the BLS-MICA chimeric protein constitutes a novel antitumor vaccine of potential application in patients with MICA-expressing tumors.