Edwin Roger Parra1, Pamela Villalobos1, Jiexin Zhang2, Carmen Behrens3, Barbara Mino1, Stephen Swisher4, Boris Sepesi4, Annika Weissferdt5, Neda Kalhor5, John Victor Heymach3, Cesar Moran5, Jianjun Zhang3, Jack Lee2, Jaime Rodriguez-Canales1, Don Gibbons6, Ignacio I Wistuba7. 1. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 7. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: iiwistuba@mdanderson.org.
Abstract
INTRODUCTION: The understanding of immune checkpoint molecules' co-expression in non-small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. METHODS: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs - 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) - placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. RESULTS: Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. CONCLUSIONS: We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.
INTRODUCTION: The understanding of immune checkpoint molecules' co-expression in non-small cell lung carcinoma (NCLC) is important to potentially design combinatorial immunotherapy approaches. METHODS: We studied 225 formalin-fixed, paraffin-embedded tumor tissues from stage I-III NCLCs - 142 adenocarcinomas (ADCs) and 83 squamous cell carcinomas (SCCs) - placed in tissue microarrays. Nine immune checkpoint markers were evaluated; four (programmed death ligand 1 [PD-L1], B7-H3, B7-H4, and indoleamine 2,3-dioxygenase 1 [IDO-1]) expressed predominantly in malignant cells (MCs) and five (inducible T cell costimulator, V-set immunoregulatory receptor, T-cell immunoglobulin mucin family member 3, lymphocyte activating 3, and OX40) expressed mostly in stromal tumor-associated inflammatory cells (TAICs). All markers were examined using a quantitative image analysis and correlated with clinicopathologic features, TAICs, and molecular characteristics. RESULTS: Using above the median value as positive expression in MCs and high density of TAICs expressing those markers, we identified higher expression of immune checkpoints in SCC than ADC. Common simultaneous expression by MCs was PD-L1 + B7-H3 + IDO-1 in ADC and PD-L1 + B7-H3, or B7-H3 + B7-H4, in SCC. TAICs expressing checkpoint were significantly higher in current smokers than in never smokers. Almost all the immune checkpoint markers showed positive correlation with TAICs expressing inflammatory cell markers. KRAS-mutant ADC specimens showed higher expression of PD-L1 in MCs and of B7-H3, T-cell immunoglobulin mucin family member 3, and IDO-1 in TAICs than wild type. Kaplan-Meier survival curves showed worse prognosis in ADC patients with higher B7-H4 expression by MCs. CONCLUSIONS: We found frequent immunohistochemical co-expression of immune checkpoints in surgically resected NCLC tumors and correlated with tumor histology, smoking history, tumor size, and the density of inflammatory cells and tumor mutational status.
Authors: Kyle G Mitchell; Edwin R Parra; David B Nelson; Jiexin Zhang; Ignacio I Wistuba; Junya Fujimoto; Jack A Roth; Mara B Antonoff Journal: J Thorac Cardiovasc Surg Date: 2019-05-17 Impact factor: 5.209
Authors: Kyle G Mitchell; Edwin R Parra; Jiexin Zhang; David B Nelson; Erin M Corsini; Pamela Villalobos; Cesar A Moran; Ferdinandos Skoulidis; Ignacio I Wistuba; Junya Fujimoto; Jack A Roth; Mara B Antonoff Journal: Ann Thorac Surg Date: 2020-05-19 Impact factor: 4.330
Authors: Pedro Rocha; Ruth Salazar; Jiexin Zhang; Debora Ledesma; Jose L Solorzano; Barbara Mino; Pamela Villalobos; Hitoshi Dejima; Dzifa Y Douse; Lixia Diao; Kyle Gregory Mitchell; Xiuning Le; Jianjun Zhang; Annikka Weissferdt; Edwin Parra-Cuentas; Tina Cascone; David C Rice; Boris Sepesi; Neda Kalhor; Cesar Moran; Ara Vaporciyan; John Heymach; Don L Gibbons; J Jack Lee; Humam Kadara; Ignacio Wistuba; Carmen Behrens; Luisa Maren Solis Journal: Cancer Immunol Immunother Date: 2021-01-08 Impact factor: 6.968