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Targets of tumor infiltrating lymphocyte reactivity in pancreatic cancer

Rieger, Jan Hendrik

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Abstract

With little to no progress in the treatment of pancreatic cancer over the past decades, novel approaches to cover the high unmet medical need are long overdue. However, the long lasting notion of PDAC being a ‘non-immunogenic’ neoplasm lacking uniform infiltration of effector lym- phocytes and holding an immunosuppressive microenvironment has so far precluded the use of adoptive T cell therapy in this malignancy. Furthermore, the overall low mutational burden of pancreatic cancer led to the assumption of decreased frequencies in immunogenic neoepi- topes targeted by T cells. Nevertheless, the recent identification of frequently occurring effector T cells recognizing their autologous tumor in pancreatic cancer indicates a potential use of PDAC derived TILs against the malignancy. In addition, exome analyses of larger patient co- horts indicated that formation of immunogenic, mutation derived epitopes in PDAC might be more frequent than previously expected. Nevertheless, to date functional analyses identifying and characterizing the epitopes recognized by pancreatic cancer TIL are yet to be carried out. Thus, we set out to develop screening approaches to reliably identify mutation derived epitopes within pancreatic cancer patients. This development was approached with two complementary strategies, first by looking into the antigens recognized by PDAC TILs and second by directly identifying the epitopes presented on the surface of the PDAC derived tumor cells. We addressed the antigen recognition by developing a novel expression based screening sys- tem. Since PDAC is frequently infiltrated by CD4+ and CD8+ T cells (both of which populations potentially mount anti tumor immune responses), combined with a low number of tumor muta- tions, we needed an approach able to screen for both, MHC-I and MHC-II restricted antigens. Therefore, we designed a system based on shuttling antigens into both, the major histocom- patibility complex (MHC)-I and -II antigen presentation pathways, in order to define the reac- tivity of PDAC TILs in a completely unbiased fashion (i.e. not depending on MHC restriction and/or epitope prediction algorithms). Furthermore, we validated the use of a targeted mass spectrometry based approach to directly identify epitopes presented on the surface of PDAC derived cells lines. In addition, the application of both approaches in a small patient cohort was used to draw initial conclusions on the feasibility of both approaches for an extension to larger patient cohorts. Taken together, the presented study describes the development and validation of screening methodologies capable of identifying antigens in the context of low mutational burden malig- nancies such as pancreatic cancer. These methodologies lay the foundation for the functional proof of concept studies of antigen reactive T cells infiltrating pancreatic cancer, opening new ways for the application of adoptive T cell transfer in this fatal disease.

Item Type: Dissertation
Supervisor: Umansky, Prof. Dr. Viktor
Place of Publication: Heidelberg
Date of thesis defense: 7 November 2019
Date Deposited: 14 Nov 2019 09:28
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
600 Technology (Applied sciences)
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