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Resistance Mechanisms in Cancer Immunotherapy

Trefny, Marcel Philipp. Resistance Mechanisms in Cancer Immunotherapy. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Cancer Immunology is considered to be one of the most important advances in oncology in the last decades. PD-(L)1–blocking antibodies have clinical activity in metastatic non–small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade. Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. In this thesis, I first present a study where peripheral blood mononuclear cells were collected from 35 patients with NSCLC receiving nivolumab monotherapy and cellular changes, cytokine levels, gene expression, and polymorphisms were compared upon treatment between responders and non-responders. We identified a genetic variant of a killer cell immunoglobulin-like receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in patients with NSCLC. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients, the progression-free survival was significantly associated with presence of the KIR3DS1 allele. In addition, we find that tumor-infiltrating NK cells from NSCLC patients express elevated levels of the immune checkpoint receptors PD-1, TIM-3, and TIGIT on their cell surface. Moreover, we find that PD-1+ NK cells co-expressed more inhibitory receptors compared to PD-1- NK cells and provide evidence that NK cell dysfunction in intratumoral NK cells correlates with NK cell PD-1 expression. Notably, treatment with anti-PD-1 blockade was able to reverse PD-L1 mediated inhibition of PD-1+ NK cells, highlighting the therapeutic potential of PD-1+ NK cells in immune checkpoint blockade. Our findings link NK cells with response to PD-1 therapy in NSCLC and reveal new potential pathways that could be exploited to improve immunotherapy for PD-1 non-responsive patients. Lastly, I developed a human model system to dissect the mechanisms that lead to T cell dysfunction in humans. Here, repetitive stimulation with a defined tumor antigen presented on tumors cells leads to T cell dysfunction resembling T cells found in human tumors on a phenotypic and transcriptional level. Through a targeted CRISPR-Cas9 knock out screen and functional validation, we discovered novel candidate genes to improve T cell effector functions. Our ex vivo model provides the community with a versatile tool to study different aspects of human T cell dysfunction ex vivo and could help to improve anti-tumour efficacy of T cell-targeted immunotherapies.
Advisors:Zippelius, Alfred and Hess, Christoph and Romero, Pedro
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Onkologie > Translationale Onkologie (Zippelius)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Onkologie > Translationale Onkologie (Zippelius)
05 Faculty of Science
UniBasel Contributors:Zippelius, Alfred and Hess, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13998
Thesis status:Complete
Number of Pages:144
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss139984
edoc DOI:
Last Modified:05 Mar 2021 05:30
Deposited On:04 Mar 2021 09:48

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