Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer

Kathleen Ducoin; Romain Oger; Linda Bilonda Mutala; Cécile Deleine; Nicolas Jouand; Juliette Desfrançois; Juliette Podevin; Emilie Duchalais; Jonathan Cruard; Houssem Benlalam; Nathalie Labarrière; Céline Bossard; Anne Jarry; Nadine Gervois-Segain

doi:10.1080/2162402X.2022.2046931

Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer

Oncoimmunology. 2022 Mar 9;11(1):2046931. doi: 10.1080/2162402X.2022.2046931. eCollection 2022.

Authors

Kathleen Ducoin^{1

2}, Romain Oger^{2

3}, Linda Bilonda Mutala^{2

3

4}, Cécile Deleine^{1

2}, Nicolas Jouand⁵, Juliette Desfrançois⁵, Juliette Podevin⁶, Emilie Duchalais⁶, Jonathan Cruard³, Houssem Benlalam^{1

2}, Nathalie Labarrière^{1

2}, Céline Bossard^{2

3

6}, Anne Jarry^{1

2}, Nadine Gervois-Segain^{1

2}

Affiliations

¹ Nantes Université, Univ Angers, INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302. F-44000 Nantes, France.
² LabEx IGO, Université de Nantes, Nantes, France.
³ Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France.
⁴ Institut Roche, Boulogne-Billancourt, France.
⁵ Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000 Nantes, France.
⁶ CHU Nantes, Department of Digestive Surgery and IMAD, Nantes, France.

Abstract

Recently, the inhibitory CD94/NKG2A receptor has joined the group of immune checkpoints (ICs) and its expression has been documented in NK cells and CD8⁺ T lymphocytes in several cancers and some infectious diseases. In colorectal cancer (CRC), we previously reported that NKG2A⁺ tumor-infiltrating lymphocytes (TILs) are predominantly CD8⁺ αβ T cells and that CD94 overexpression and/or its ligand HLA-E were associated with a poor prognosis. This study aimed to thoroughly characterize the NKG2A⁺ CD8⁺ TIL subpopulation and document the impact of NKG2A on anti-tumor responses in CRC. Our findings highlight new features of this subpopulation: (i) enrichment in colorectal tumors compared to paired normal colonic mucosa, (ii) their character as tissue-resident T cells and their majority terminal exhaustion status, (iii) co-expression of other ICs delineating two subgroups differing mainly in the level of NKG2A expression and the presence of PD-1, (iv) high functional avidity despite reduced proliferative capacity and finally (v) inhibition of anti-tumor reactivity that is overcome by blocking NKG2A. From a clinical point of view, these results open a promising alternative for immunotherapies based on NKG2A blockade in CRC, which could be performed alone or in combination with other IC inhibitors, adoptive cell transfer or therapeutic vaccination.

Keywords: CD8+ TILs; NKG2A; colorectal cancer; immune checkpoint inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes* / immunology
CD8-Positive T-Lymphocytes* / pathology
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / immunology
Colorectal Neoplasms* / pathology
Humans
Killer Cells, Natural / immunology
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / pathology
NK Cell Lectin-Like Receptor Subfamily C* / immunology

Substances

KLRC1 protein, human
NK Cell Lectin-Like Receptor Subfamily C

Grants and funding

This work was supported by grants awarded by the Ligue contre le cancer Grand Ouest (Comités du Finistère, de Loire-Atlantique, Côtes d’Armor, Morbihan et Loir-et-Cher), DHU Oncogreffe, CHU Nantes (RC14-0416-1) and Cancéropôle Grand Ouest (Réseau Immunothérapie - Amgen RC16-0212-1). This work was performed in the context of the “LabEx IGO” program (ANR-11-LABX-0016-01);Ligue Contre le Cancer;