Intratumoral injection of dendritic cells engineered to produce interleukin-12 for colon cancer treatment. Low cd80 surface expression is a tumor immunoescape mechanism

Résumé

INTRATUMORAL INJECTION OF DENDRITIC CELLS ENGINEERED TO PRODUCE INTERLEUKIN-12 FOR COLON CÁNCER TREATMENT. LOW CD80 SURFACE EXPRESSION IS A TUMOR IMMUNOESCAPE MECHANISM RESUMEN In this work, we have found that: (i) repeated injections of dendritic cells (DC), genetically engineered to produce interleukin-12, as opposed to a single injection, achieved better antitumor efficacy both against the injected and a distantly implanted tumor, (ii) that the use of semiallogeneic DC, that are mismatched in one MHC haplotype with the tumor host, showed slightly better efficacy and (i i i) that the combination of this treatment with systemic injections of anti-CDl37 (4-lBB) monoclonal antibodies achieved potent combined effects, leading to the eradication of concomitant untreated lesions in most cases. We have also demonstrated that unmutated CD80 is spontaneously expressed at low levies on mouse colon carcinoma cell lines and on other tumor cell lines of various tissue origins. Silencing of CD80 by interfering RNA led to loss of tumorigenicity of CT26 colon carcinoma in immunocompetent mice, but not in immunodeficient mice. CT26 tumor cells bind CTLA-4lg but much more faintly a similar CD28ig chimeric protein, thus providing an explanation for the dominant inhibitory effects on tumor immunity displayed by CD80 at those levies of expression. CD80 negative tumor cell lines such as MC38 colon carcinoma and Bl6 melanoma, express CD80 at dim levies during in vivo growth in syngeneic mice. Therefore, as it occurs with DC, low CD80 surface expression seems to advantage cancer cells against the immune system, while higher levies result in increased antitumor immunity, thus providing an explanation for the low levies of CD80 expression described in various human mal ignancies