Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL

Ziju Y. Xu-Monette, Min Xiao, Qingyan Au*, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodríguez-Perales, Raul Torres-Ruiz, Ganiraju C. Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkær, Wayne Tam, Hua You, Govind Bhagat, Eric D. Hsi & 13 others Maurilio Ponzoni, Andres J.M. Ferreri, Michael B. Møller, Miguel A. Piris, J. Han van Krieken, Jane Norma Winter, Jason R. Westin, Lan V. Pham, L. Jeffrey Medeiros, George Z. Rassidakis, Yong Li, Gordon J. Freeman, Ken H. Young

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immu-nofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/ PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

Original languageEnglish (US)
Pages (from-to)644-657
Number of pages14
JournalCancer Immunology Research
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Tumor Microenvironment
Lymphoma, Large B-Cell, Diffuse
T-Lymphocytes
Immunotherapy
Neoplasms
Cellular Microenvironment
Survival
Gene Expression Profiling
Vincristine
B-Cell Lymphoma
Prednisone
Natural Killer Cells
Doxorubicin
Cyclophosphamide
Up-Regulation
Biomarkers
Macrophages
Ligands

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Xu-Monette, Ziju Y. ; Xiao, Min ; Au, Qingyan ; Padmanabhan, Raghav ; Xu, Bing ; Hoe, Nicholas ; Rodríguez-Perales, Sandra ; Torres-Ruiz, Raul ; Manyam, Ganiraju C. ; Visco, Carlo ; Miao, Yi ; Tan, Xiaohong ; Zhang, Hongwei ; Tzankov, Alexandar ; Wang, Jing ; Dybkær, Karen ; Tam, Wayne ; You, Hua ; Bhagat, Govind ; Hsi, Eric D. ; Ponzoni, Maurilio ; Ferreri, Andres J.M. ; Møller, Michael B. ; Piris, Miguel A. ; Han van Krieken, J. ; Winter, Jane Norma ; Westin, Jason R. ; Pham, Lan V. ; Jeffrey Medeiros, L. ; Rassidakis, George Z. ; Li, Yong ; Freeman, Gordon J. ; Young, Ken H. / Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 4. pp. 644-657.
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abstract = "PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immu-nofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/ PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.",
author = "Xu-Monette, {Ziju Y.} and Min Xiao and Qingyan Au and Raghav Padmanabhan and Bing Xu and Nicholas Hoe and Sandra Rodr{\'i}guez-Perales and Raul Torres-Ruiz and Manyam, {Ganiraju C.} and Carlo Visco and Yi Miao and Xiaohong Tan and Hongwei Zhang and Alexandar Tzankov and Jing Wang and Karen Dybk{\ae}r and Wayne Tam and Hua You and Govind Bhagat and Hsi, {Eric D.} and Maurilio Ponzoni and Ferreri, {Andres J.M.} and M{\o}ller, {Michael B.} and Piris, {Miguel A.} and {Han van Krieken}, J. and Winter, {Jane Norma} and Westin, {Jason R.} and Pham, {Lan V.} and {Jeffrey Medeiros}, L. and Rassidakis, {George Z.} and Yong Li and Freeman, {Gordon J.} and Young, {Ken H.}",
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Xu-Monette, ZY, Xiao, M, Au, Q, Padmanabhan, R, Xu, B, Hoe, N, Rodríguez-Perales, S, Torres-Ruiz, R, Manyam, GC, Visco, C, Miao, Y, Tan, X, Zhang, H, Tzankov, A, Wang, J, Dybkær, K, Tam, W, You, H, Bhagat, G, Hsi, ED, Ponzoni, M, Ferreri, AJM, Møller, MB, Piris, MA, Han van Krieken, J, Winter, JN, Westin, JR, Pham, LV, Jeffrey Medeiros, L, Rassidakis, GZ, Li, Y, Freeman, GJ & Young, KH 2019, 'Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL', Cancer Immunology Research, vol. 7, no. 4, pp. 644-657. https://doi.org/10.1158/2326-6066.CIR-18-0439

Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL. / Xu-Monette, Ziju Y.; Xiao, Min; Au, Qingyan; Padmanabhan, Raghav; Xu, Bing; Hoe, Nicholas; Rodríguez-Perales, Sandra; Torres-Ruiz, Raul; Manyam, Ganiraju C.; Visco, Carlo; Miao, Yi; Tan, Xiaohong; Zhang, Hongwei; Tzankov, Alexandar; Wang, Jing; Dybkær, Karen; Tam, Wayne; You, Hua; Bhagat, Govind; Hsi, Eric D.; Ponzoni, Maurilio; Ferreri, Andres J.M.; Møller, Michael B.; Piris, Miguel A.; Han van Krieken, J.; Winter, Jane Norma; Westin, Jason R.; Pham, Lan V.; Jeffrey Medeiros, L.; Rassidakis, George Z.; Li, Yong; Freeman, Gordon J.; Young, Ken H.

In: Cancer Immunology Research, Vol. 7, No. 4, 01.04.2019, p. 644-657.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL

AU - Xu-Monette, Ziju Y.

AU - Xiao, Min

AU - Au, Qingyan

AU - Padmanabhan, Raghav

AU - Xu, Bing

AU - Hoe, Nicholas

AU - Rodríguez-Perales, Sandra

AU - Torres-Ruiz, Raul

AU - Manyam, Ganiraju C.

AU - Visco, Carlo

AU - Miao, Yi

AU - Tan, Xiaohong

AU - Zhang, Hongwei

AU - Tzankov, Alexandar

AU - Wang, Jing

AU - Dybkær, Karen

AU - Tam, Wayne

AU - You, Hua

AU - Bhagat, Govind

AU - Hsi, Eric D.

AU - Ponzoni, Maurilio

AU - Ferreri, Andres J.M.

AU - Møller, Michael B.

AU - Piris, Miguel A.

AU - Han van Krieken, J.

AU - Winter, Jane Norma

AU - Westin, Jason R.

AU - Pham, Lan V.

AU - Jeffrey Medeiros, L.

AU - Rassidakis, George Z.

AU - Li, Yong

AU - Freeman, Gordon J.

AU - Young, Ken H.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immu-nofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/ PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

AB - PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immu-nofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/ PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

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