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Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor
- Source :
- Oncoimmunology. 5(2)
- Publication Year :
- 2015
-
Abstract
- T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction.
- Subjects :
- 0301 basic medicine
Tumor microenvironment
biology
medicine.medical_treatment
T cell
CD3
Immunology
03 medical and health sciences
030104 developmental biology
Cytokine
medicine.anatomical_structure
Oncology
Folate receptor
Cancer research
medicine
biology.protein
Immunology and Allergy
Cytokine secretion
Folate receptor 1
Cytotoxicity
Original Research
Subjects
Details
- ISSN :
- 21624011
- Volume :
- 5
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Oncoimmunology
- Accession number :
- edsair.doi.dedup.....35e6c0cbb53317ad51a1ffcfefb4a564