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
Abstract
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: 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: 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.