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Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity

Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the “cancer-immunity cycle” in the pan-cancer setting in order to understand the immune landscape of metastati...

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Autores principales: Kato, Shumei, Okamura, Ryosuke, Kumaki, Yuichi, Ikeda, Sadakatsu, Nikanjam, Mina, Eskander, Ramez, Goodman, Aaron, Lee, Suzanna, Glenn, Sean T., Dressman, Devin, Papanicolau-Sengos, Antonios, Lenzo, Felicia L., Morrison, Carl, Kurzrock, Razelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028323/
https://www.ncbi.nlm.nih.gov/pubmed/32117584
http://dx.doi.org/10.1080/2162402X.2019.1708065
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author Kato, Shumei
Okamura, Ryosuke
Kumaki, Yuichi
Ikeda, Sadakatsu
Nikanjam, Mina
Eskander, Ramez
Goodman, Aaron
Lee, Suzanna
Glenn, Sean T.
Dressman, Devin
Papanicolau-Sengos, Antonios
Lenzo, Felicia L.
Morrison, Carl
Kurzrock, Razelle
author_facet Kato, Shumei
Okamura, Ryosuke
Kumaki, Yuichi
Ikeda, Sadakatsu
Nikanjam, Mina
Eskander, Ramez
Goodman, Aaron
Lee, Suzanna
Glenn, Sean T.
Dressman, Devin
Papanicolau-Sengos, Antonios
Lenzo, Felicia L.
Morrison, Carl
Kurzrock, Razelle
author_sort Kato, Shumei
collection PubMed
description Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the “cancer-immunity cycle” in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P < .01). In conclusion, cancer-immunity cycle biomarker evaluation was feasible in diverse solid tumors. High expression of alternative checkpoints TIM-3 and VISTA and of the macrophage-associated markers CD68 were associated with significantly worse PFS after anti-PD-1/PD-L1-based therapies. Most patients had distinct and complex immune expression profiles suggesting the need for customized combinations of immunotherapy.
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spelling pubmed-70283232020-02-28 Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity Kato, Shumei Okamura, Ryosuke Kumaki, Yuichi Ikeda, Sadakatsu Nikanjam, Mina Eskander, Ramez Goodman, Aaron Lee, Suzanna Glenn, Sean T. Dressman, Devin Papanicolau-Sengos, Antonios Lenzo, Felicia L. Morrison, Carl Kurzrock, Razelle Oncoimmunology Original Research Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the “cancer-immunity cycle” in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P < .01). In conclusion, cancer-immunity cycle biomarker evaluation was feasible in diverse solid tumors. High expression of alternative checkpoints TIM-3 and VISTA and of the macrophage-associated markers CD68 were associated with significantly worse PFS after anti-PD-1/PD-L1-based therapies. Most patients had distinct and complex immune expression profiles suggesting the need for customized combinations of immunotherapy. Taylor & Francis 2020-02-17 /pmc/articles/PMC7028323/ /pubmed/32117584 http://dx.doi.org/10.1080/2162402X.2019.1708065 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Kato, Shumei
Okamura, Ryosuke
Kumaki, Yuichi
Ikeda, Sadakatsu
Nikanjam, Mina
Eskander, Ramez
Goodman, Aaron
Lee, Suzanna
Glenn, Sean T.
Dressman, Devin
Papanicolau-Sengos, Antonios
Lenzo, Felicia L.
Morrison, Carl
Kurzrock, Razelle
Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title_full Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title_fullStr Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title_full_unstemmed Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title_short Expression of TIM3/VISTA checkpoints and the CD68 macrophage-associated marker correlates with anti-PD1/PDL1 resistance: implications of immunogram heterogeneity
title_sort expression of tim3/vista checkpoints and the cd68 macrophage-associated marker correlates with anti-pd1/pdl1 resistance: implications of immunogram heterogeneity
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028323/
https://www.ncbi.nlm.nih.gov/pubmed/32117584
http://dx.doi.org/10.1080/2162402X.2019.1708065
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