Restoration of anti-tumor immunity through anti-MICA antibodies elicited with a chimeric protein

TORRES, NICOLÁS IGNACIO; REGGE, MARÍA VICTORIA; SECCHIARI, FLORENCIA; FRIEDRICH, ADRIÁN; SPALLANZANI, RAÚL GERMÁN; RAFFO IRAOLAGOITÍA, XIMENA LUCÍA; NÚÑEZ, SOL YANEL; SIERRA, JESSICA MARIEL; ZIBLAT, ANDREA; SANTILLI, MARÍA CECILIA; GILIO, NICOLÁS; ALMADA, EVANGELINA; LAUCHE, CONSTANZA; PARDO, ROMINA PAOLA; DOMAICA, CAROLINA INÉS; FUERTES, MERCEDES BEATRIZ; MADAUSS, KEVIN PATRICK; HANCE, KEN W.; GLOGER, ISRAEL; ZYLBERMAN, VANESA; GOLDBAUM, FERNANDO ALBERTO; ZWIRNER, NORBERTO WALTER

Journal for ImmunoTherapy of Cancer

Springer Nature

Lugar: New Jersey; Año: 2020 vol. 8 p. 233 - 233

2051-1426

Background: Natural killer and cytotoxic CD8+ T cells are major players during anti-tumor 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 over-expressed 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 anti-tumor immunity through the induction of direct anti-tumor effects (antibody-dependent cell-mediated cytotoxicity, ADCC) and scavenging 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 anti-tumor 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 anti-tumor 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 intra-tumoral M1/pro-inflammatory 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 anti-tumor immune response towards an anti-tumoral/pro-inflammatory phenotype. Hence, the BLS-MICA chimeric protein constitutes a novel anti-tumor vaccine of potential application in patients with MICA-expressing tumors.