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Background <p>Patients with lung cancer brain metastases can benefit from immune checkpoint inhibitors (ICI). However, intracranial responses are often limited and not always concordant with activity seen in extracranial disease. Defects in IFNγ signaling and HLA class-I antigen presentation machinery (APM) on malignant cells can drive immune evasion and ICI resistance, and have traditionally been viewed as interdependent. The possible role of these alterations in non-small cell lung cancer (NSCLC) brain progression remains poorly understood.</p> Methods <p>Using multiplex quantitative immunofluorescence, we measured and spatially mapped IFNγ signaling markers (pSTAT1 and IRF1) and multiple HLA class-I APM components (β2M, PSMB8, PSMB9, PSMB10, TAP1, TAP2, Tapasin, Calreticulin, and ERp57) in cancer cells and neighboring non-malignant stromal cells from two patient cohorts, including primary tumors, intra- and extra-cranial NSCLC metastases. We also studied tumor-infiltrating lymphocyte (TILs) subpopulations in the cohorts, performed whole transcriptomic analysis of parental human NSCLC H2030 cells and their brain metastatic counterpart H2030-BrM3, and expanded the results using spatial transcriptomics of human tumors.</p> Results <p>We found comparable levels of IFNγ signaling markers in primary and metastatic lesions and marked downregulation of multiple APM components in metastases, some of which were restricted to the brain. Downregulation of HLA class-I APM components was associated with reduced effector TILs and worse survival. Analysis of human parental H2030 and brain metastatic H2030-BrM3 lung adenocarcinoma cells showed comparable signaling responses after IFNγ stimulation and reduced HLA class-I APM markers in metastatic cells. Transcriptomic analysis of primary/metastatic cells and human tumors identified differential expression of multiple genes associated with HLA class-I APM downregulation.</p> Conclusions <p>Our results reveal that APM downregulation is a prominent feature of NSCLC brain metastases, is independent from local IFNγ signaling defects and is associated with unfavorable clinical features. We also identified candidate modulators of the APM pathway in brain metastases with potential translational significance.</p>

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NSCLC brain metastases exhibit reduced HLA-I antigen presentation machinery and immune evasion independent of IFNγ signaling defects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Noelia Vilariño,
  • Miguel López de Rodas,
  • Maria Villalba-Esparza,
  • Barani Kumar Rajendran,
  • Boyu Huang,
  • Sara Hijazo-Pechero,
  • Adrien Costantini,
  • Kishu Ranjan,
  • Javier Ramos-Paradas,
  • Benjamin Y. Lu,
  • Ernest Nadal,
  • Sarah B. Goldberg,
  • Don X. Nguyen,
  • Kurt A. Schalper

摘要

Background

Patients with lung cancer brain metastases can benefit from immune checkpoint inhibitors (ICI). However, intracranial responses are often limited and not always concordant with activity seen in extracranial disease. Defects in IFNγ signaling and HLA class-I antigen presentation machinery (APM) on malignant cells can drive immune evasion and ICI resistance, and have traditionally been viewed as interdependent. The possible role of these alterations in non-small cell lung cancer (NSCLC) brain progression remains poorly understood.

Methods

Using multiplex quantitative immunofluorescence, we measured and spatially mapped IFNγ signaling markers (pSTAT1 and IRF1) and multiple HLA class-I APM components (β2M, PSMB8, PSMB9, PSMB10, TAP1, TAP2, Tapasin, Calreticulin, and ERp57) in cancer cells and neighboring non-malignant stromal cells from two patient cohorts, including primary tumors, intra- and extra-cranial NSCLC metastases. We also studied tumor-infiltrating lymphocyte (TILs) subpopulations in the cohorts, performed whole transcriptomic analysis of parental human NSCLC H2030 cells and their brain metastatic counterpart H2030-BrM3, and expanded the results using spatial transcriptomics of human tumors.

Results

We found comparable levels of IFNγ signaling markers in primary and metastatic lesions and marked downregulation of multiple APM components in metastases, some of which were restricted to the brain. Downregulation of HLA class-I APM components was associated with reduced effector TILs and worse survival. Analysis of human parental H2030 and brain metastatic H2030-BrM3 lung adenocarcinoma cells showed comparable signaling responses after IFNγ stimulation and reduced HLA class-I APM markers in metastatic cells. Transcriptomic analysis of primary/metastatic cells and human tumors identified differential expression of multiple genes associated with HLA class-I APM downregulation.

Conclusions

Our results reveal that APM downregulation is a prominent feature of NSCLC brain metastases, is independent from local IFNγ signaling defects and is associated with unfavorable clinical features. We also identified candidate modulators of the APM pathway in brain metastases with potential translational significance.