TY - JOUR
T1 - Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non–small cell lung cancer
AU - MD Anderson Lung Cancer Immune Microenvironment Working Group
AU - Mitchell, Kyle G.
AU - Parra, Edwin R.
AU - Nelson, David B.
AU - Zhang, Jiexin
AU - Wistuba, Ignacio I.
AU - Fujimoto, Junya
AU - Roth, Jack A.
AU - Antonoff, Mara B.
AU - Corsini, Erin M.
AU - Vaporciyan, Ara A.
AU - Hofstetter, Wayne L.
AU - Mehran, Reza J.
AU - Swisher, Stephen G.
AU - Rice, David C.
AU - Sepesi, Boris
AU - Walsh, Garrett L.
AU - Behrens, Carmen
AU - Kalhor, Neda
AU - Weissferdt, Annikka
AU - Moran, Cesar A.
AU - Lee, J. Jack
N1 - Funding Information:
This work was supported in part by the Cancer Prevention Research Institute of Texas Multi-Investigator Research Awards (RP160668, IIW), National Institutes of Health / National Cancer Institute through the University of Texas Lung Specialized Programs of Research Excellence Grant (P50CA70907, IIW), generous philanthropic donations by the Mason family and anonymous donors, and departmental funding.
Funding Information:
This work was supported in part by the Cancer Prevention Research Institute of Texas Multi-Investigator Research Awards (RP160668, IIW), National Institutes of Health/National Cancer Institute through the University of Texas Lung Specialized Programs of Research Excellence Grant (P50CA70907, IIW), generous philanthropic donations by the Mason family and anonymous donors, and departmental funding.Roth discloses unrelated relationships with Genprex (equity, consulting) and Varian (grant support). All other authors have nothing to disclose with regard to commercial support. This work was supported in part by the Cancer Prevention Research Institute of Texas Multi-Investigator Research Awards (RP160668, IIW), National Institutes of Health/ National Cancer Institute through the University of Texas Lung Specialized Programs of Research Excellence Grant (P50CA70907, IIW), generous philanthropic donations by the Mason family and anonymous donors, and departmental funding. The MD Anderson Lung Cancer Immune Microenvironment Working Group coauthors include Erin M. Corsini, MD, Ara A. Vaporciyan, MD, Wayne L. Hofstetter, MD, Reza J. Mehran, MD, Stephen G. Swisher, MD, David C. Rice, MD, Boris Sepesi, MD, Garrett L. Walsh, Carmen Behrens, MD, Neda Kalhor, MD, Annikka Weissferdt, MD, DrMed, Cesar A. Moran, MD, and J. Jack Lee, PhD, MS, DDS. This work was supported in part by the Cancer Prevention Research Institute of Texas Multi-Investigator Research Awards (RP160668, IIW), National Institutes of Health/ National Cancer Institute through the University of Texas Lung Specialized Programs of Research Excellence Grant (P50CA70907, IIW), generous philanthropic donations by the Mason family and anonymous donors, and departmental funding.
Funding Information:
This work was supported in part by the Cancer Prevention Research Institute of Texas Multi-Investigator Research Awards (RP160668, IIW), National Institutes of Health/National Cancer Institute through the University of Texas Lung Specialized Programs of Research Excellence Grant (P50CA70907, IIW), generous philanthropic donations by the Mason family and anonymous donors, and departmental funding.Roth discloses unrelated relationships with Genprex (equity, consulting) and Varian (grant support). All other authors have nothing to disclose with regard to commercial support. The MD Anderson Lung Cancer Immune Microenvironment Working Group coauthors include Erin M. Corsini, MD, Ara A. Vaporciyan, MD, Wayne L. Hofstetter, MD, Reza J. Mehran, MD, Stephen G. Swisher, MD, David C. Rice, MD, Boris Sepesi, MD, Garrett L. Walsh, Carmen Behrens, MD, Neda Kalhor, MD, Annikka Weissferdt, MD, DrMed, Cesar A. Moran, MD, and J. Jack Lee, PhD, MS, DDS.
Publisher Copyright:
© 2019 The American Association for Thoracic Surgery
PY - 2019/9
Y1 - 2019/9
N2 - Objectives: Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer. Methods: Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset. Results: A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P <.001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P =.013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P <.001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival. Conclusions: Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.
AB - Objectives: Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer. Methods: Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997-2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset. Results: A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P <.001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P =.013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P <.001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival. Conclusions: Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.
KW - Ki67
KW - immune checkpoints
KW - immune microenvironment
KW - non–small cell lung cancer
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U2 - 10.1016/j.jtcvs.2019.04.084
DO - 10.1016/j.jtcvs.2019.04.084
M3 - Article
C2 - 31235357
AN - SCOPUS:85067573934
SN - 0022-5223
VL - 158
SP - 911-919.e6
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
IS - 3
ER -