PhD Scientific Days 2023

Molecular Sciences - Posters B

Overcoming Resistance to Immune-Checkpoint Blockade due to Deficient Antigen Presentation in Melanoma Using In Vivo CrispR Screens

Előadó neve

Lakatos, Alexandra, MSc

Neptun code

Q6A6I1

Előadó munkahelye

Semmelweis University, Department of Physiology

Előadó telefonszáma

+36305514464

Előadó e-mail címe

lakatos.alexandra@phd.semmelweis.hu

Az előadás címe

Overcoming Resistance to Immune-Checkpoint Blockade due to Deficient Antigen Presentation in Melanoma Using In Vivo CrispR Screens

Szerző(k) neve és munkahelye

Alexandra Lakatos1, Dorottya Pál1, Anna Sára Lengyel, MD.2, Petra Péter 1, Botond Szabolcs 1, Elmar Lutz 1, David E. Fisher MD,PhD.3 , Lajos V. Kemény MD, PhD.1,2,3

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

Molecular Sciences - Posters B

Language of the presentation

Hungarian

Preferred session

Molecular Sciences

Összefoglaló szövege

Introduction: Despite recent developments in the field of immune-oncology by the introduction of immune- checkpoint blockade (ICB) in the management of melanoma, resistance to ICB therapies still poses a tremendous problem. Loss of antigen presentation is one of the most common resistant mechanisms to ICB due to the lack of proper neoantigen recognition by CD8 T cells.

Aims: We hypothesize that in the absence of MHC-I expression, additional, T cell independent mechanisms could be utilized in the management of melanoma and we aim to identify novel therapeutic approaches to overcome resistance associated with loss of antigen presentation.

Methods and Results: We created an in vivo mouse model of melanoma to study anti-tumor immune responses against tumor cells lacking MHC-I expression by genetically deleting B2M gene. Using this model of antigen presentation deficiency, we have observed a difference in growth of the antigen presentation deficient melanoma cell line in immune competent and immune compromised mice, suggesting that anti-tumor immunity occurs even in the absence of MHC-I mediated antigen presentation to T cells.
Next, we have performed an in vivo crispr screen using an epigenetic gRNA library targeting 600 genes involved in epigenetics to identify genes that are associated with response or resistance to immunological selection pressure that is independent of CD8 T cells and identified gRNAs targeting 20 genes are underrepresented in tumors harvested from immunocompetent mice compared with tumors isolated from immunodeficient mice.

Conclusion: The B2M deficient mouse model of melanoma can be used to study MHC-I independent immune clearance in immunocompetent mice. We have identified some promising targets to increase efficacy of ICB in B2M loss melanoma cells. Next, we aim to repeat the screen using a genome-wide library to identify additional potential targets and to validate the hits from our pilot screen. Our approach may identify cancer-specific regulators of T cell- independent melanoma clearance and may lead to the discovery of potential novel therapeutic targets.

Funding: L.V.K. is a recipient of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and is supported by the Hungarian National Research, Development and Innovation Office (OTKA FK138696) grant, a STIA-KFI grant from Semmelweis University. The project has received funding from the EU’s Horizon 2020 research and innovation program under grant agreement no. 739593.

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine

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.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7350

Start

11:06

End

11:11

Authors (legacy)

Alexandra Lakatos1, Dorottya Pál1, Anna Sára Lengyel, MD.2, Petra Péter 1, Botond Szabolcs 1, Elmar Lutz 1, David E. Fisher MD,PhD.3 , Lajos V. Kemény MD, PhD.1,2,3

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.