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Poster session 09

15P - CBL E3 ubiquitin ligases are key inhibitory regulators in PD-1/LAG-3 co-signaling in human cancers, targeted through bispecific co-blockade

Date

21 Oct 2023

Session

Poster session 09

Topics

Basic Science

Tumour Site

Presenters

Luisa Chocarro

Citation

Annals of Oncology (2023) 34 (suppl_2): S187-S214. 10.1016/S0923-7534(23)01931-2

Authors

L. Chocarro1, L. Fernández-Rubio1, M.J. Garcia Granda1, E. Blanco Palmeiro1, A.I. Bocanegra Gondan1, M. Echaide1, M. Garnica1, M. Zuazo1, C. Johnston2, C.J. Edwards2, J. Leggs2, A. Pierce2, H. Arasanz3, R. Vera3, K. Ausin4, E. Santamaría4, J. Fernández-Irigoyen4, G. Kochan1, D. Escors1

Author affiliations

  • 1 Oncoimmunology Unit, Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 - Pamplona/ES
  • 2 Crescendo Biologics Ltd, Crescendo Biologics Ltd, CB22 3AT - Cambridge/GB
  • 3 Medical Oncology Unit, University Hospital of Navarra, 31008 - Pamplona/ES
  • 4 Proteomics Platform, Proteored-isciii, Navarrabiomed-Fundación Miguel Servet, Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 - Pamplona/ES

Resources

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Abstract 15P

Background

A significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells.

Methods

A high-throughput screening was performed of PD-1/LAG-3 multiomic expression profiles in public databases of human cancer biopsies, to establish relationships between infiltrating tumor-infiltrating PD-1/LAG-3 T cells with biomarkers both in T cells and within the tumour microenvironment. These results were validated in engineered T-cell lines with constitutively active PD-1, LAG-3 pathways, and their combination, analysed by high-throughput quantitative proteomics and validated by conventional molecular techniques on primary T cells from NSCLC patients.

Results

The high-throughput multiomic human cancers screening and the experimental proteomic T cell lines uncovered a strong PD-1/LAG-3 dysfunctionality signature that was found which regulated immune, proteomic, metabolic, genetic, and epigenetic pathways. These mainly relied on differential regulation of E3 ubiquitin ligases CBL-B and C-CBL. Notably, LAG-3 expression has never been associated to CBL ubiquitin ligases before.

Conclusions

PD-1/LAG-3 co-signaling profile uncovers a highly dysfunctional regulated programme. Co-blockade with a bispecific drug but not with a combination of anti-PD-1/anti-LAG-3 antibodies achieved both CBL-B and C-CBL inhibition, reverting T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD- 1 blockade. These results will help identifying the mechanisms of intrinsic resistance to PD-1 blockade mediated by LAG-3 co-signaling.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Navarrabiomed.

Funding

This research was supported by: The Spanish Association against Cancer (AECC), PROYE16001ESCO; Instituto de Salud Carlos III (ISCIII)-FEDER Project grants FIS PI20/00010, COV20/00000, and TRANSPOCART ICI19/00069; Biomedicine Project Grant from the Department of Health of the Government of Navarre-FEDER funds (BMED 050-2019, 51-2021); Strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Union Horizon 2020 ISOLDA project, under grant agreement ID: 848166. L.C. is financed by Instituto de Salud Carlos III (ISCIII), co-financed by FEDER funds, "Contratos PFIS: contratos predoctorales de formación en investigación en salud" (FI21/00080); M.E. is financed by the Navarrabiomed- Fundación Miguel Servet predoctoral contract.

Disclosure

C.J. Edwards: Other, Personal, Other, Declares to be inventor of the Humabody CB213 (WO/2019/158942. 603 Crescendo Biologics Ltd.): Crescendo Biologics. J. Leggs: Other, Declares to be e inventor of the Humabody CB213 (WO/2019/158942. 603 Crescendo Biologics Ltd.): Crescendo Biologics. D. Escors: Other, Declares to be e inventor of the Humabody CB213 (WO/2019/158942. 603 Crescendo Biologics Ltd.): Navarrabiomed. All other authors have declared no conflicts of interest.

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