Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

Amanda N. Ruggieri; Mark Yarchoan; Subir Goyal; Yuan Liu; Elad Sharon; Helen X. Chen; Brian M. Olson; Chrystal M. Paulos; Bassel F. El-Rayes; Shishir K. Maithel; Nilofer S. Azad; Gregory B. Lesinski

doi:10.1158/1078-0432.CCR-22-1123

Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

Amanda N. Ruggieri, Mark Yarchoan, Subir Goyal, Yuan Liu, Elad Sharon, Helen X. Chen, Brian M. Olson, Chrystal M. Paulos, Bassel F. El-Rayes, Shishir K. Maithel, Nilofer S. Azad, Gregory B. Lesinski

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/ PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design:Weexamined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progressionfree survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

Original language	English (US)
Pages (from-to)	4336-4345
Number of pages	10
Journal	Clinical Cancer Research
Volume	28
Issue number	19
DOIs	https://doi.org/10.1158/1078-0432.CCR-22-1123
State	Published - Oct 1 2022

ASJC Scopus subject areas

General Medicine

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10.1158/1078-0432.CCR-22-1123

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Ruggieri, A. N., Yarchoan, M., Goyal, S., Liu, Y., Sharon, E., Chen, H. X., Olson, B. M., Paulos, C. M., El-Rayes, B. F., Maithel, S. K., Azad, N. S., & Lesinski, G. B. (2022). Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer. Clinical Cancer Research, 28(19), 4336-4345. https://doi.org/10.1158/1078-0432.CCR-22-1123

Ruggieri, AN, Yarchoan, M, Goyal, S, Liu, Y, Sharon, E, Chen, HX, Olson, BM, Paulos, CM, El-Rayes, BF, Maithel, SK, Azad, NS & Lesinski, GB 2022, 'Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer', Clinical Cancer Research, vol. 28, no. 19, pp. 4336-4345. https://doi.org/10.1158/1078-0432.CCR-22-1123

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title = "Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer",

abstract = "Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/ PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design:Weexamined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progressionfree survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.",

author = "Ruggieri, {Amanda N.} and Mark Yarchoan and Subir Goyal and Yuan Liu and Elad Sharon and Chen, {Helen X.} and Olson, {Brian M.} and Paulos, {Chrystal M.} and El-Rayes, {Bassel F.} and Maithel, {Shishir K.} and Azad, {Nilofer S.} and Lesinski, {Gregory B.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = oct,

day = "1",

doi = "10.1158/1078-0432.CCR-22-1123",

language = "English (US)",

volume = "28",

pages = "4336--4345",

journal = "Clinical Cancer Research",

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T1 - Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

AU - Ruggieri, Amanda N.

AU - Yarchoan, Mark

AU - Goyal, Subir

AU - Liu, Yuan

AU - Sharon, Elad

AU - Chen, Helen X.

AU - Olson, Brian M.

AU - Paulos, Chrystal M.

AU - El-Rayes, Bassel F.

AU - Maithel, Shishir K.

AU - Azad, Nilofer S.

AU - Lesinski, Gregory B.

PY - 2022/10/1

Y1 - 2022/10/1

N2 - Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/ PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design:Weexamined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progressionfree survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

AB - Purpose: Biliary tract cancers (BTC) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibition (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/ PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC. Experimental Design:Weexamined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and peripheral blood mononuclear cells (PBMC) were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC. Results: At baseline, the soluble factors platelet-derived growth factor B (PDGF)-BB, placental growth factor (PlGF)-1, IL5, and IL17A were elevated in patients with BTC compared with healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival (OS) in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and progressionfree survival (PFS). Higher baseline levels of IL23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. Conclusions: This work represents a comprehensive analysis of peripheral immune features in patients with BTC and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for patients with advanced BTC.

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Combined MEK/PD-L1 Inhibition Alters Peripheral Cytokines and Lymphocyte Populations Correlating with Improved Clinical Outcomes in Advanced Biliary Tract Cancer

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