Abstract
Immune resistance may arise from both genetic instability and tumor heterogeneity. Microenvironmental stresses such as hypoxia and various resistance mechanisms promote carcinoma cell plasticity. AXL, a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, is widely expressed in human cancers and increasingly recognized for its role in cell plasticity and drug resistance. To investigate mechanisms of immune resistance, we studied multiple human lung cancer clones derived from a model of hypoxia-induced tumor plasticity that exhibited mesenchymal or epithelial features. We demonstrate that AXL expression is increased in mesenchymal lung cancer clones. Expression of AXL in the cells correlated with increased cancer cell-intrinsic resistance to both natural killer (NK)- and cytotoxic T lymphocyte (CTL)-mediated killing. A small-molecule targeting AXL sensitized mesenchymal lung cancer cells to cytotoxic lymphocyte-mediated killing. Mechanistically, we showed that attenuation of AXL-dependent immune resistance involved a molecular network comprising NF-κB activation, increased ICAM1 expression, and upregulation of ULBP1 expression coupled with MAPK inhibition. Higher ICAM1 and ULBP1 tumor expression correlated with improved patient survival in two non-small cell lung cancer (NSCLC) cohorts. These results reveal an AXL-mediated immune-escape regulatory pathway, suggest AXL as a candidate biomarker for tumor resistance to NK and CTL immunity, and support AXL targeting to optimize immune response in NSCLC.
Highlights
Lung cancer is the third most frequent cancer and the first cause of cancer-related death worldwide [1, 2]
Increase in AXL expression associated with resistance to lysis It has previously been shown that AXL is highly expressed in lung cancers that have undergone epithelial– mesenchymal transition (EMT) [15]
We examined whether the increased expression of ULBP1 and ICAM1 observed upon AXL inhibition could explain the increased susceptibility to lymphocyte-mediated lysis
Summary
Lung cancer is the third most frequent cancer and the first cause of cancer-related death worldwide [1, 2]. Lung carcinoma is heterogeneous and composed of subpopulations of cancer cells, or clones, with distinct molecular and phenotypic features. The immune system plays a role during tumor development, with the interplay between cancer cells and their tumor microenvironment. The latter contributes to the development of refractoriness through mechanisms preventing cytotoxic immune effector T cells and natural killer (NK) cells from reaching and destroying their targets [4]. Carcinoma cells can undergo molecular and phenotypic changes referred to as carcinoma cell plasticity, which contributes to heterogeneity in tumors. Our understanding of the mechanistic links between carcinoma cell plasticity, heterogeneity, and the emergence of tumor immune escape remains poor due to the limited number of preclinical models that recapitulate carcinoma cell phenotypic diversity in the tumor mass
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