PhD Scientific Days 2025
Budapest, 7-9 July 2025
Poster Session III. - C: Molecular Medicine
Overcoming Immune Checkpoint Blockade Resistance in Melanoma through In Vivo CRISPR Screening of Antigen Presentation Deficiencies
Előadó neve
Lakatos Alexandra
Neptun code
Q6A6I1
Előadó munkahelye
Semmelweis University, Faculty of Medicine, Department of Physiology
Előadó telefonszáma
+36305514464
Előadó e-mail címe
lakatos.alexandra@phd.semmelweis.hu
Az előadás címe
Overcoming Immune Checkpoint Blockade Resistance in Melanoma through In Vivo CRISPR Screening of Antigen Presentation Deficiencies
Szerző(k) neve és munkahelye
Alexandra Lakatos1, Dorottya Pál1, Botond Szabolcs1,2, Katalin Buday1, David E. Fisher3, Lajos V. Kemény1,2,3
1: HCEMM-SU Translational Dermatology Research Group, Department of Physiology, Semmelweis University, 37-47. Tűzoltó street 1094 Budapest, Hungary
2: Department of Dermatology, Venerology and Dermatooncology, Semmelweis University, 41. Mária street 1085 Budapest, Hungary
3: Cutaneous Biology Research Center, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
Bemutatás módja
Poszter
Szekció
Poster Session III. - C: Molecular Medicine
Language of the presentation
Hungarian
Preferred session
Molecular Medicine
Összefoglaló szövege
Introduction: Despite recent developments in immuno-oncology through the introduction of immune checkpoint blockade (ICB) in melanoma treatment, resistance to ICB therapy remains a major challenge. Loss of antigen presentation is one of the most common resistance mechanisms that disrupt CD8 T cell-mediated neoantigen recognition.
Aims: We hypothesize that in the absence of MHC-I expression, an alternative T cell-independent mechanism may be leveraged in melanoma treatment. Our aim is to identify novel therapeutic strategies to overcome resistance mechanisms associated with impaired antigen presentation.
Methods: We developed an in vivo melanoma model lacking MHC-I expression by deleting the B2M gene to study immune responses in antigen presentation–deficient tumors. To identify genes involved in MHC-I–independent immune responses, we performed an in vivo CRISPR screen using a gRNA library targeting 600 epigenetic regulators.
Results: We observed distinct tumor growth patterns in immunocompetent versus immunodeficient mice, suggesting that anti-tumor immunity can occur independently of MHC-I–mediated CD8⁺ T cell recognition. From CRISPR library targeting 600 genes, gRNAs corresponding to 20 genes were significantly depleted in tumors from immunocompetent mice, indicating their potential role in modulating immune resistance independent of CD8⁺ T cells. Based on bioinformatic analysis we prioritized the top four candidate genes for further investigation. For each of these genes, single-cell knockout clones were generated. Validation is currently underway at DNA, RNA and protein levels to confirm gene disruption and assess functional relevance.
Conclusion: The B2M-deficient melanoma model allows investigation of MHC-I–independent tumor immunity in immunocompetent mice. Our CRISPR screen identified genes linked to T cell–independent elimination of tumor cells. We are planning to perform a genome-wide screen
to uncover additional targets. This strategy may reveal cancer-specific immune evasion pathways and support novel approaches to enhance ICB efficacy in B2M-deficient tumors.
Funding: This work was supported by the Hungarian National Research, Development and Innovation Office (OTKA FK138696), the EU Horizon 2020 program (739593), and the Lendület “Momentum” Program of the Hungarian Academy of Sciences (LP2024-12/2024).
University
Semmelweis University
Supervisor
Lajos Vince Kemény MD, PhD
Publication of my abstract
I do not give consent to the publication of my abstract on the website of the congress.
phd.section.field
in doctoral studies after complex exam (PhD)
Kind
Szabad
Status
elfogadva
Accepted presentation method
poszter
Előadás fájl jóváhagyás
nem rendelkezett róla
Előadó
7350
Start
14:54
End
15:00