NKG2D · CO-OPTION OF THE NKG2D LYMPHOCYTE RECEPTOR AS AN ONCOPROTEIN PROMOTING CANCER STEM CELL TRANSDIFFERENTIATION AND CANCER AUTONOMY
FP7 — People (Marie Curie Actions)
- Duration
- 2014-01-01 → 2018-01-01
- EU contribution
- €261,326
- Participants
- 1
- Scheme
- MC-IOF
Lines connect the coordinator with its partners.
Results in brief
CO-OPTION OF THE NKG2D LYMPHOCYTE RECEPTOR AS AN ONCOPROTEIN PROMOTING CANCER STEM CELL TRANSDIFFERENTIATION AND CANCER AUTONOMY
Comprehensive characterization of the immune landscape in non-small cell lung cancer The success of immune checkpoint inhibitors (ICI) for non- small cell lung cancer (NSCLC) has galvanized the field. Unfortunately, just ~20% of patients benefit from novel therapies and underlying mechanisms for treatment failure are mostly unknown. ICI therapy likely fails for one of two reasons: (1) an antigen-driven immune response is not present or (2) an antigen-driven immune response is present, but immune suppressive factors reside within the tumor microenvironment (TME) that derail an otherwise effective immune response. Lung cancer, the leading cause of cancer deaths, is a heterogeneous disease classified by histologic subtypes, with adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) representing the majority of NSCLC. Just as the anatomical location and mutational signature of the NSCLC subtypes differ, one would expect that the immune cell composition and function would also differ. A strong foundational knowledge of the immune cell composition in NSCLC, will likely prove prerequisite to realizing the full potential of such reagents. To evaluate the complexity of the immune landscape in NSCLC we examined tumor and non-adjacent lung tissue in a cohort of 73 patients. We used flow cytometry, fluorescent multiplex immunohistochemistry and gene expression analysis to comprehensively profile the immune cell content and function in attempts to identify the dominant immune suppressive factors. Further, we performed T cell receptor sequencing to delineate the frequency with which antigen-driven immune responses exist. The additional analysis of somatic mutations, gene fusions and signaling pathways of the same cohort allowed the comprehensive characterization of NSCLC. We could show that many immune cell types are significantly increased in tumor, when compared to non-adjacent lung. Cluster analysis identified patient groups with immune inactive and exhausted adaptive immunity and immune cell compositions are unique for NSCLC subtypes. In SCCA we observed a neutrophil predominant signature with additional increased infiltration of Treg when compared to ADCA. SCCA displays immune suppressive cell content, indicated by high expression of exhaustion markers on T-cells (PD-1, TIM3). Further, a more clonal TCRβ repertoire was observed in SCCA, indicating the presence of an antigen-driven immune response. Further, we identified that neutrophils constrain adaptive immune responses and neutrophils were the most abundant immune cell type in NSCLC specimens. A strong negative correlation between neutrophil and CD8+ cellular content was observed. Notably, this association did not exist in non-adjacent lung tissue, strongly suggesting that this is a tumor-specific phenomenon. This multidimensional dataset provides evidence that the immune landscape present within different NSCLC subtypes displays unique phenotypes and identifying the immunosuppressive factors in different subsets will be important for successful immune-based therapy.
Data: CORDIS, © European Union
Project objective
The stimulatory NKG2D lymphocyte receptor expressed on natural killer cells and T cells and its tumor-associated ligands enable the immune system to recognize and destroy cancer cells. This role of NKG2D is well recognized and efforts are underway to target NKG2D and its ligands for cancer therapy. However, cancers adopt diverse strategies to safeguard their survival. With advanced human cancers, NKG2D ligand expression favors tumor progression, which has been ascribed to ligand-induced immune evasion. In a surprising conceptual twist, Dr. Spies’ laboratory at the Fred Hutchinson Cancer Research Center has found that cancer cells themselves express NKG2D together with its DAP10 signaling adaptor. Above-threshold expression of NKG2D–DAP10 in ligand-bearing tumor lines activates oncogenic signaling cascades and induces differentiation changes characteristic of the epithelial-mesenchymal transition (EMT), a cellular reprogramming process that leads to increased cancer cell motility and metastatic dissemination. Intertwined with EMT is the generation of self-renewing cancer stem cells (CSCs), which are main culprits of failed cancer therapies. These findings challenge current concepts as cancer cells may co-opt NKG2D as an oncoprotein serving their own benefit.In a preliminary assessment, this role is supported by significant correlations between proportions of cancer cells that are positive for surface NKG2D and criteria of tumor progression. This proposal seeks to establish that cancer cell NKG2D has a major role in the development of CSCs. The experimental approach involves tissue culture-based studies using model tumor cell lines and functional testing of patient-derived NKG2D bearing CSCs for their tumor forming capacity in a mouse model. The results may have profound biomedical implications by establishing a previously unrecognized mechanism that promotes tumor autonomy, and may impact translational approaches targeting NKG2D or its ligands for cancer therapy.
Original text from CORDIS.
Participants
- MEDIZINISCHE UNIVERSITAT GRAZ · GrazCoordinatorAustria
Links
Data: CORDIS, © European Union