Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein.
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.
['Torres|Nicolas|N|', 'Regge|María Victoria|MV|', 'Secchiari|Florencia|F|', 'Friedrich|Adrián David|AD|', 'Spallanzani|Raúl Germán|RG|', 'Raffo Iraolagoitia|Ximena Lucía|XL|', 'Núñez|Sol Yanel|SY|', 'Sierra|Jessica Mariel|JM|', 'Ziblat|Andrea|A|', 'Santilli|María Cecilia|MC|', 'Gilio|Nicolás|N|', 'Almada|Evangelina|E|', 'Lauche|Constanza|C|', 'Pardo|Romina|R|', 'Domaica|Carolina Inés|CI|', 'Fuertes|Mercedes Beatriz|MB|', 'Madauss|Kevin Patrick|KP|', 'Hance|Kenneth W|KW|', 'Gloger|Israel S|IS|', 'Zylberman|Vanesa|V|', 'Goldbaum|Fernando Alberto|FA|', 'Zwirner|Norberto Walter|NW|0000-0001-7098-359X']
D000818:Animals D000911:Antibodies, Monoclonal D000920:Antibody-Dependent Cell Cytotoxicity D002002:Brucella D005260:Female D015395:Histocompatibility Antigens Class I D008223:Lymphoma D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009097:Multienzyme Complexes D055655:NK Cell Lectin-Like Receptor Subfamily K D011993:Recombinant Fusion Proteins D014407:Tumor Cells, Cultured D001749:Urinary Bladder Neoplasms
immunology