Abstract
BackgroundT-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation.MethodsTC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction.ResultsCombination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress.ConclusionsThese data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release.
Highlights
T-cell mediated immunotherapy brought clinical success for many cancer patients
We cultured the HPV16 E6 and E7 transformed TC1 cancer line and the B16F10 melanoma line under nutrient proficient, oxygen deprived (OD) (1% oxygen), glucose deprived (GD) (0.5 mM), or the combination of oxygen- and glucose-deprived (OGD) conditions, simulating the physiological levels measured in the microenvironment of solid cancers [11, 21,22,23]
major histocompatibility complex class I (MHC-I) surface display and CD8 T cell recognition are restored by inhibitors of Phosphoinositide 3-kinases (PI3Ks) we investigated the impact of the PI3K inhibitors on MHC-I expression on tumor cells cultured under OGD conditions and compared this to tumor cells cultured under normal conditions (Fig. 6a-d)
Summary
T-cell mediated immunotherapy brought clinical success for many cancer patients. downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Recent advances in immunotherapy have led to great clinical successes in multiple cancer types, especially advanced melanoma and non-small cell lung carcinoma. T cell based immunotherapy, like checkpoint blockade therapy, adoptive T cell transfer, and DC vaccination all rely on the surface presentation of tumor-associated or tumor-specific (neo-)antigens on cancer cells by major histocompatibility complex class I (MHC-I) molecules [1, 2]. Many cancer types downregulate MHC-I surface display as primary or acquired immunological resistance through molecular mechanisms affecting IFNy signaling, including loss-of-function mutations in the Janus kinase (JAK) signal transducers, mutations in the IFNy receptor, and alterations in APLNR and PTPN2 genes that control IFNy sensing [4,5,6,7,8]. The impact of tumor microenvironmental metabolic cues on IFNy receptor signaling and immune recognition of cancer cells is a largely unexplored area of research
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