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

Abstract

BackgroundNatural 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.MethodsWe generated a highly immunogenic chimeric protein (BLS-MICA) consisting of human MICA fused to the lumazine synthase fromBrucellaspp (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.ResultsImmunization 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.ConclusionsImmunization 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.

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

“…In addition to the effects on T lymphocytes, hypoxia also affects the function of natural killer (NK) cells. There is substantial evidence that hypoxia suppresses the cytotoxic effect of NK cells in tumors [101]. Upregulation of HIF-1α within the tumor can lead to decreased expression of the natural killer group 2 member D (NKG2D) receptor on NK and T cells, leading to immune evasion and impaired tumor cell killing [101,102].…”

Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy

“…The direct impact of hypoxia on NK cells may involve HIF-1α upregulation via the activation of the phosphatidylinositol 3 kinase (PI3K)/mTOR signaling pathway [27]. Furthermore, hypoxic tumor cells, via HIF-1α, can upregulate the expression of the metalloproteinase ADAM10, which is responsible for the shedding of the natural killer group 2, member D (NKG2D) ligand major histocompatibility complex (MHC) class I chain-related molecule A (MICA) from the tumor cell surface [28]. Soluble MICA can downregulate the expression of the NKG2D activating receptor on NK and T cells, resulting in tumor evasion from the immune system [28].…”

“…Furthermore, hypoxic tumor cells, via HIF-1α, can upregulate the expression of the metalloproteinase ADAM10, which is responsible for the shedding of the natural killer group 2, member D (NKG2D) ligand major histocompatibility complex (MHC) class I chain-related molecule A (MICA) from the tumor cell surface [28]. Soluble MICA can downregulate the expression of the NKG2D activating receptor on NK and T cells, resulting in tumor evasion from the immune system [28]. Moreover, hypoxia can downregulate the expression and function of the major activating NK-cell receptors (NK p30, NK p44, NK p46, and NKG2D).…”

Leveraging NKG2D Ligands in Immuno-Oncology

“…MICA is expressed in a wide variety of tumors ( 91 , 101 – 110 ). RNA sequencing (seq) data indicate that MICA is the NKG2DL that exhibits the highest expression in, from example, lung, colorectal, stomach, liver and breast cancers ( 111 ). Also, MICA exhibits a very low tumor mutational burden, suggesting that its expression is not subject to DNA editing to confer some kind of adaptive advantage to tumors.…”

“…Prophylactic active immunization with BLS-MICA significantly delayed the growth of MICA-expressing tumors in part due to the ability to promote scavenging of sMICA from mouse sera. Passive immunization experiments demonstrated that such effect was mediated by anti-MICA Ab that mediated in vitro and in vivo ADCC, and that tilted the balance of tumor-infiltrating cells towards an anti-tumoral/pro-inflammatory phenotype characterized by an increased presence of TAM with an M1-skewed phenotype and antigen-experienced CTL ( 111 ). Therefore, immunization with BLS-MICA induced therapeutic anti-MICA Ab that constitute a “two-in-one” strategy as they promote tumor elimination by ADCC and interfere with a tumor immune escape through scavenging of sMICA.…”