GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells

Yannick S Rakké, Lucia Campos Carrascosa, Adriaan A van Beek, Valeska de Ruiter, Rachelle S van Gemerden, Michail Doukas, Pascal G Doornebosch, Maarten Vermaas, Susan Ter Borg, Erwin van der Harst, Peter Paul L O Coene, Mike Kliffen, Dirk J Grünhagen, Cornelis Verhoef, Jan N M IJzermans, Jaap Kwekkeboom, Dave Sprengers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)
31 Downloads (Pure)


BACKGROUND & AIMS: In contrast to mismatch repair deficient colorectal carcinoma (CRC), MMR proficient (pMMR) CRC does not respond to immune checkpoint blockade. We studied immune checkpoint stimulation via glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) on ex vivo functionality of human tumor-infiltrating lymphocytes (TIL) isolated from pMMR primary CRC and liver metastases (CRLM).

METHODS: Using lymphocytes from resected tumor, adjacent tissues, and peripheral blood mononuclear cells (PBMC) of 132 pMMR primary CRC or CRLM patients, we determined GITR expression and the in vitro T-cell agonistic activity of recombinant GITR ligation.

RESULTS: Here, we show that GITR was overexpressed on TIL when compared with other stimulatory immune checkpoints (4-1BB, OX40). Its expression was enhanced in TIL compared with PBMC and adjacent tissues. Among CD4 + TIL, GITR expression was primarily expressed by CD45RA - FoxP3 hi activated regulatory T cells. Within CD8 + TIL, GITR was predominantly expressed on functionally exhausted and putative tumor-reactive CD103 + CD39 + TIL. Strikingly, recombinant GITRL reinvigorated ex vivo TIL responses by significantly enhancing CD4 + and CD8 + TIL numbers. Dual treatment with GITRL and nivolumab (anti-PD1) enhanced CD8 + TIL expansion compared with GITRL monotherapy. Moreover, GITRL/anti-PD1 dual therapy further improved anti-PD1-mediated reinvigoration of interferon gamma secretion by exhausted CD8 TIL from primary CRC.

CONCLUSIONS: GITR is overexpressed on CD4 + and CD8 + TIL from pMMR CRC and CRLM. Agonistic targeting of GITR enhances ex vivo human TIL functionality and may therefore be a promising approach for novel monotherapy or combined immunotherapies in primary pMRR CRC and CRLM.

Original languageEnglish
Pages (from-to)77-97
Number of pages21
JournalCellular and Molecular Gastroenterology and Hepatology
Issue number1
Early online date23 Sept 2022
Publication statusPublished - Jan 2023

Bibliographical note

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.


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