Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor
| Autor: | M von Bergwelt-Baildon, Victor Levitsky, Philipp Müller, Pablo Umana, Alfred Zippelius, Viola Heinzelmann-Schwarz, Anton Belousov, Vaios Karanikas, Franziska Uhlenbrock, Andreas Roller, Spasenija Savic, Marina Bacac, Didier Lardinois, Jens Schreiner, Wolfgang Moersig, Petra Herzig, Daniela S. Thommen, Pavel Pisa, Christian Klein |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
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 |
| Zdroj: | Oncoimmunology. 5(2) |
| ISSN: | 2162-4011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|