LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures
Open accessAbstract
Despite the success of immunotherapy using checkpoint blockade, many patients with solid tumors remain refractory to these treatments. In human cancer, the experimental options to investigate the specific effects of antibodies blocking inhibitory receptors are limited and it is still unclear which cell types are involved. We addressed the question whether the direct interaction between T cells and tumor cells can be enforced through blocking a set of inhibitory receptors including PD-1, TIM-3, BTLA and LAG-3, blocked either individually or in dual combinations with the anti-PD-1 antibody, and to determine the condition that induces maximal T cell function preventing tumor cell proliferation. Using short-term Melan-A-specific or autologous re-stimulations, checkpoint blockade did not consistently increase cytokine production by tumor-derived expanded T cells. We next set up a 5-day co-culture assay with autologous melanoma cell lines and expanded tumor infiltrating T cells, originating from tumor specimens obtained from 6 different patients. Amongst all combos tested, we observed that blockade of LAG-3 alone, and more strongly when combined with PD-1 blockade, enforced T cell responses and tumor cell growth control. The combination of anti-LAG-3 plus anti-PD-1 acted through CD8 T cells and led to increased IFNγ production and cytotoxic capacity. Our results show that LAG-3 and PD-1 are regulating the direct interaction between tumor cells and autologous T cells, suggesting that therapy effects may be promoted by enhanced access of the corresponding blocking reagents to the tumor microenvironment.
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Other ICIs such as α-LAG-3, α-PVRIG, α-TIGIT, α-Siglec-10 also synergized with α-PD-1/PD-L1 in enhancing TIL function and suppressing tumor growth.
“Besides α-TIM-3, other ICIs such as α-LAG-3, α-PVRIG, α-TIGIT, α- Siglec-10 also synergized with α-PD-1/PD-L1 in enhancing TIL function and suppressing tumor growth [161–164].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [161]
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The role of immune checkpoint molecules in cancers
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Challenges and advances of immune checkpoint therapy
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Breaking the mold: Overcoming resistance to immune checkpoint inhibitors
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The Immune landscape of pediatric solid tumorsPreprint
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Inmunoterapia en Melanoma: Rol de TIGIT y LAG-3 en el microambiente inmune antitumoral
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Cancer Immunotherapy: A Systemic Review
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Additional file 1 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056669
Additional file 7 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056687
Additional file 2 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056672
Additional file 6 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056684
Additional file 4 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056678
Additional file 5 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056681
Additional file 3 of The immune landscape of solid pediatric tumors
Sherif, S., Roelands, J. P., Mifsud, W., Ahmed, E. I., Raynaud, C. M., Rinchai, D., Sathappan, A., Maaz, A., Saleh, A., Ozer, E., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20056675
Ma, Z., Sun, J. Y., Wu, X., Shang, C., & Li, B. (2026) · Oncogenesis · doi:10.1038/s41389-026-00603-7
Potential Target Line, FGFR3, EGFR and Immune Checkpoint Axis for Bladder Cancer Therapy
Manikandan, A., Walter, C. E. J., Durairajan, S., Kumaresan, N., Balakrishnan, A., Saravanan, A., Walter, J. E., & Johnson, T. (2026) · Immuno · doi:10.3390/immuno6020036
- Authors
- Gestermann, N., Saugy, D., Martignier, C., Tillé, L., Fuertes Marraco, S. A., Zettl, M., Tirapu, I., Speiser, D. E., & Verdeil, G.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Lausanne
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Verdeil, Grégory
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2020-01
- Volume
- 9
- Issue
- 1
- Pages
- 1736792-1736792
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC7422827
- OpenAlex
- W3010808413
- Cited by
- 69
- References
- 40
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 18 · 2023: 12 · 2022: 16 · 2021: 9 · 2020: 2
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc)
- IRIS (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Krebsliga Schweiz (3679-08-2015, 3971-08-2016)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_173197, 310030_182680)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- LAG-3, PD-1, immune checkpoint blockade, melanoma, tumor-infiltrating T cells, TIM-3, BTLA, CD8+ T cells, interferon-gamma, cytotoxicity, tumor microenvironment, anti-PD-1
- MeSH terms
- Humans, Immunotherapy, Lymphocyte Activation, Melanoma, Coculture Techniques, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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