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Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.
Wessel, Remziye E; Ageeb, Nardin; Obeid, Joseph M; Mauldin, Ileana S; Goundry, Kate A; Hanson, Gabriel F; Hossain, Mahdin; Lehman, Chad; Gentzler, Ryan D; Wages, Nolan A; Slingluff, Craig L; Bullock, Timothy N J; Dolatshahi, Sepideh; Brown, Michael G.
Afiliação
  • Wessel RE; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
  • Ageeb N; Department of Biology, University of Virginia, Charlottesville, Virginia, USA.
  • Obeid JM; Department of Thoracic Surgery, Temple University Hospital, Philadelphia, Pennsylvania, USA.
  • Mauldin IS; Department of Surgery, University of Virginia, Charlottesville, Virginia, USA.
  • Goundry KA; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
  • Hanson GF; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
  • Hossain M; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
  • Lehman C; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
  • Gentzler RD; Department of Medicine, Hematology and Oncology, University of Virginia, Charlottesville, Virginia, USA.
  • Wages NA; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA.
  • Slingluff CL; Department of Surgery, University of Virginia, Charlottesville, Virginia, USA.
  • Bullock TNJ; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
  • Dolatshahi S; Department of Pathology, University of Virginia, Charlottesville, Virginia, USA.
  • Brown MG; Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA sdolatshahi@virginia.edu.
J Immunother Cancer ; 12(9)2024 Sep 18.
Article em En | MEDLINE | ID: mdl-39299754
ABSTRACT

BACKGROUND:

Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.

METHODS:

We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis.

RESULTS:

Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells.

CONCLUSIONS:

Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent colocalization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Matadoras Naturais / Antígenos de Histocompatibilidade Classe I / Carcinoma Pulmonar de Células não Pequenas / Linfócitos T CD8-Positivos / Neoplasias Pulmonares Limite: Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Matadoras Naturais / Antígenos de Histocompatibilidade Classe I / Carcinoma Pulmonar de Células não Pequenas / Linfócitos T CD8-Positivos / Neoplasias Pulmonares Limite: Female / Humans / Male Idioma: En Ano de publicação: 2024 Tipo de documento: Article