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The target antigen determines the mechanism of acquired resistance to T cell based therapies

ABSTRACT: Immunotherapy is a revolution in cancer treatment. Despite its success, cancer patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen is important and can be decisive in the success of the clinical response, particularly when resistance emerge. T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. It is assumed that, as all TCBs have the same mechanism of action, mechanisms of resistance are independent of the tumor antigen. Using gastric CEA+/HER2+ MKN45 cells as a model and TCBs directed against CEA or HER2, here we show that the mechanism of resistance to a T cell-based therapy is dependent on the tumor antigen. Acquired resistant models to a high-affinity CEA-targeted TCB exhibit a reduction of CEA antigen levels due to transcriptional silencing, which is reversible upon 5-AZA treatment in vitro and in vivo. In contrast, a HER2-TCB resistant model maintains HER2 levels as HER2 downregulation led to an impairment of proliferation. Furthermore, using this latter model, we identify the disruption of the interferon-gamma signaling as the cause of resistance to killing by active T lymphocytes. Our results unveil different mechanisms of acquired resistance to TCBs depending on the selected antigen, which will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210592 | GEO | 2022/12/23

REPOSITORIES: GEO

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Project description:These experiments were done as part of a larger study that investigated the mode of action of T-cell bispecific (TCB) antibodies (including CEA-TCB [cibisatamab]) by characterizing molecular and cellular features of immune cells and tumors following TCB treatment in vivo in humanized mice and syngeneic tumor models. To characterize the molecular parameters associated with CEA-TCB treatment we performed bulk RNA sequencing of CEA-TCB-treated and untreated tumors derived from MKN-45 tumor-bearing humanized mice. Tumor tissue was analyzed after seven consecutive TCB treatments and compared to matching controls. RNA sequencing analysis revealed a clear distinction between CEA-TCB-treated and control animals, with several genes being upregulated in tumors treated with CEA-TCB as compared to controls. Among the top 15 upregulated genes in CEA-TCB-treated tumors there were many reflective of a strong T-cell activation, migration, immune cell response (CXCL13, GNLY, GZMB, CXCL10, IDO1, SLA, CD2, TRBC2, TIGIT, IL2RB, CXCL9, CX3CL1, CCL4L2, and CD3E). Among the top downregulated ones we found keratin 6A and keratin 20 (KRT6A and KRT20) suggestive of the reduction of tumor cells as the result of TCB-mediated killing. A Gene Set Enrichment Analysis (GSEA) was conducted that further enabled identification of the main biological pathways upon CEA-TCB treatment and confirmed that the main Gene Ontology families that characterize the TCB response consist of T-cell activation (Response to interferon gamma; Adaptive Immune Response; T-cell activation; Inflammatory Response; Activation of Immune response; Cytokine secretion) and migration (Leukocyte Migration; Regulation of Cell Adhesion). We also noticed upregulation of many major histocompatibility class II molecules that are known to be expressed on antigen presenting cells (HLA-DRA, HLA-DRB5, and HLA-DRB1) along with CX3CL1 (fractalkine, a known monocyte/T-cell attractant molecule) and CSF1 (colony stimulating factor 1, macrophage) suggestive of myeloid cell recruitment and activation at tumor sites post TCB treatment. The signature appeared to be robust, as components of the signature were confirmed using complementary techniques: RNA expression analysis and protein expression as determined by flow cytometry and multiplex analysis.

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The target antigen determines the mechanism of acquired resistance to T cell based therapies

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