Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer

Abstract Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inh...

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Autores principales:	Ryan J. Slovak, Hong-Jai Park, William M. Kamp, Johannes M. Ludwig, Insoo Kang, Hyun S. Kim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c3f1eaec71aa4d68a08a5f210792e245
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spelling	oai:doaj.org-article:c3f1eaec71aa4d68a08a5f210792e2452021-12-02T13:24:26ZCo-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer10.1038/s41598-021-85810-52045-2322https://doaj.org/article/c3f1eaec71aa4d68a08a5f210792e2452021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85810-5https://doaj.org/toc/2045-2322Abstract Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.Ryan J. SlovakHong-Jai ParkWilliam M. KampJohannes M. LudwigInsoo KangHyun S. KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryan J. Slovak Hong-Jai Park William M. Kamp Johannes M. Ludwig Insoo Kang Hyun S. Kim Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
description	Abstract Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.
format	article
author	Ryan J. Slovak Hong-Jai Park William M. Kamp Johannes M. Ludwig Insoo Kang Hyun S. Kim
author_facet	Ryan J. Slovak Hong-Jai Park William M. Kamp Johannes M. Ludwig Insoo Kang Hyun S. Kim
author_sort	Ryan J. Slovak
title	Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
title_short	Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
title_full	Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
title_fullStr	Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
title_full_unstemmed	Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
title_sort	co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c3f1eaec71aa4d68a08a5f210792e245
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Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer

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