دورية أكاديمية
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.
| العنوان: | 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. |
|---|---|
| المؤلفون: | Wessel RE; Department of Biomedical Engineering, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia 22908., Ageeb N; Department of Biology, UVA, Charlottesville, Virginia 22908., Obeid JM; Department of Thoracic Surgery, Temple University Hospital, Philadelphia, Pennsylvania 19140., Mauldin I; Department of Surgery, UVA School of Medicine, Charlottesville, Virginia 22908., Goundry KA; Department of Biomedical Engineering, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia 22908., Hanson GF; Department of Biomedical Engineering, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia 22908., Hossain M; Beirne B. Carter Center for Immunology Research, UVA School of Medicine, Charlottesville, Virginia 22908., Lehman C; Beirne B. Carter Center for Immunology Research, UVA School of Medicine, Charlottesville, Virginia 22908., Gentzler RD; Department of Medicine, Hematology and Oncology, UVA School of Medicine, Charlottesville, Virginia 22908., Wages NA; Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia 23298-0032., Slingluff CL Jr; Department of Surgery, UVA School of Medicine, Charlottesville, Virginia 22908., Bullock TNJ; Beirne B. Carter Center for Immunology Research, UVA School of Medicine, Charlottesville, Virginia 22908.; Department of Pathology, UVA School of Medicine, Charlottesville, Virginia 22908., Dolatshahi S; Department of Biomedical Engineering, University of Virginia (UVA) School of Medicine, Charlottesville, Virginia 22908.; Beirne B. Carter Center for Immunology Research, UVA School of Medicine, Charlottesville, Virginia 22908., Brown MG; Beirne B. Carter Center for Immunology Research, UVA School of Medicine, Charlottesville, Virginia 22908.; Department of Medicine, Nephrology, UVA School of Medicine, Charlottesville, Virginia 22908.; Center for Immunity, Inflammation and Regenerative Medicine, UVA School of Medicine, Charlottesville, Virginia 22908.; Department of Microbiology, Immunology and Cancer Biology, UVA School of Medicine, Charlottesville, Virginia 22908. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 25. Date of Electronic Publication: 2024 Jun 25. |
| نوع المنشور: | Journal Article; Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Background: MHC 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 intra- and inter-tumoral 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 (DFS) (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. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ + NK cells with other IFNγ + lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated. Competing Interests: Competing interests – CLS - Research support to UVA from Celldex (funding, drug), Merck (funding, drug), Theraclion (device staff support); Funding to UVA from Polynoma for PI role on the MAVIS Clinical Trial; Funding to UVA for roles on Scientific Advisory Boards for Immatics and CureVac. CLS receives licensing fee payments through the UVA Licensing and Ventures Group for patents for peptides used in cancer vaccines. RDG – Research support to UVA from Pfizer, Amgen, Chugai, Merck, AstraZeneca, Janssen, Daiichi Sankyo, Alliance Foundation, Takeda, ECOG/ACRIN, Jounce Therapeutics, Bristol Myers Squibb, SWOG, Helsinn, Dizal Pharmaceuticals, and Mirati. RDG received payment for service on Scientific Advisory Boards including AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanofi, Oncocyte, Jazz Pharmaceuticals, Blueprint Medicines, and Merus. |
| معلومات مُعتمدة: | P30 CA044579 United States CA NCI NIH HHS; T32 CA163177 United States CA NCI NIH HHS; T32 GM145443 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: CD8 T cells; MHC class I; cell co-localization; interferon-gamma; intratumor heterogeneity; multiplex immunofluorescence; natural killer cells; patient survival; spatial analysis; systems immunology; tissue micro-array; tumor-infiltrating lymphocytes |
| تواريخ الأحداث: | Date Created: 20240709 Latest Revision: 20240715 |
| رمز التحديث: | 20240715 |
| مُعرف محوري في PubMed: | PMC11230195 |
| DOI: | 10.1101/2024.02.20.581048 |
| PMID: | 38979183 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2692-8205 |
|---|---|
| DOI: | 10.1101/2024.02.20.581048 |