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

doi:10.1016/j.jcmgh.2022.09.007

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 journal › Article › Academic › peer-review

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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: 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 language	English
Pages (from-to)	77-97
Number of pages	21
Journal	Cellular and Molecular Gastroenterology and Hepatology
Volume	15
Issue number	1
Early online date	23 Sept 2022
DOIs	https://doi.org/10.1016/j.jcmgh.2022.09.007
Publication status	Published - Jan 2023

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GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T CellsFinal published version, 3.46 MBLicence: CC BY

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Rakké, Y. S., Campos Carrascosa, L., van Beek, A. A., de Ruiter, V., van Gemerden, R. S., Doukas, M., Doornebosch, P. G., Vermaas, M., Ter Borg, S., van der Harst, E., Coene, P. P. L. O., Kliffen, M., Grünhagen, D. J., Verhoef, C., IJzermans, J. N. M., Kwekkeboom, J., & Sprengers, D. (2023). GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells. Cellular and Molecular Gastroenterology and Hepatology, 15(1), 77-97. https://doi.org/10.1016/j.jcmgh.2022.09.007

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

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: 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. ",

author = "Rakk{\'e}, {Yannick S} and {Campos Carrascosa}, Lucia and {van Beek}, {Adriaan A} and {de Ruiter}, Valeska and {van Gemerden}, {Rachelle S} and Michail Doukas and Doornebosch, {Pascal G} and Maarten Vermaas and {Ter Borg}, Susan and {van der Harst}, Erwin and Coene, {Peter Paul L O} and Mike Kliffen and Gr{\"u}nhagen, {Dirk J} and Cornelis Verhoef and IJzermans, {Jan N M} and Jaap Kwekkeboom and Dave Sprengers",

year = "2023",

month = jan,

doi = "10.1016/j.jcmgh.2022.09.007",

language = "English",

volume = "15",

pages = "77--97",

journal = "Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier Inc.",

number = "1",

}

Rakké, YS, Campos Carrascosa, L, van Beek, AA, de Ruiter, V, van Gemerden, RS, Doukas, M, Doornebosch, PG, Vermaas, M, Ter Borg, S, van der Harst, E, Coene, PPLO, Kliffen, M, Grünhagen, DJ , Verhoef, C , IJzermans, JNM, Kwekkeboom, J & Sprengers, D 2023, 'GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells', Cellular and Molecular Gastroenterology and Hepatology, vol. 15, no. 1, pp. 77-97. https://doi.org/10.1016/j.jcmgh.2022.09.007

GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells. / Rakké, Yannick S; Campos Carrascosa, Lucia; van Beek, Adriaan A et al.
In: Cellular and Molecular Gastroenterology and Hepatology, Vol. 15, No. 1, 01.2023, p. 77-97.

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

TY - JOUR

T1 - GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells

AU - Rakké, Yannick S

AU - Campos Carrascosa, Lucia

AU - van Beek, Adriaan A

AU - de Ruiter, Valeska

AU - van Gemerden, Rachelle S

AU - Doukas, Michail

AU - Doornebosch, Pascal G

AU - Vermaas, Maarten

AU - Ter Borg, Susan

AU - van der Harst, Erwin

AU - Coene, Peter Paul L O

AU - Kliffen, Mike

AU - Grünhagen, Dirk J

AU - Verhoef, Cornelis

AU - IJzermans, Jan N M

AU - Kwekkeboom, Jaap

AU - Sprengers, Dave

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

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U2 - 10.1016/j.jcmgh.2022.09.007

DO - 10.1016/j.jcmgh.2022.09.007

M3 - Article

C2 - 36155259

SN - 2352-345X

VL - 15

SP - 77

EP - 97

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

IS - 1

ER -

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

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