Hatipoglu, Emine;
(2022)
Deciphering the Immune Landscape in Renal Cell Carcinoma and in Anti-PD-1 Therapy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Antigen recognition and T-cell mediated cytotoxicity are major tenets of cancer immunology that are not fully understood in clear-cell renal cell carcinoma (ccRCC). We evaluated multiregional treatment naïve nephrectomy samples from 27 patients as well as bloods samples from 21 and normal kidney tissue from 11 patients from the TRACERx Renal (TRAcking Cancer Evolution through therapy [Rx]) study via high dimensional flow cytometry. Results showed that the T cells in the tumour, normal kidney and blood have different phenotypes and differentiation patterns. A predominantly exhausted CD8 cell phenotype with expression of PD-1, TIM-3, Eomes, CD38 and CD39 was seen in the tumour immune microenvironment. ADAPTeR is a phase II study evaluating nivolumab (anti-PD1 antibody) in patients with treatment-naive metastatic ccRCC. Immunophenotyping by using high dimensional flow cytometry and multiplex immunofluorescence in addition to T cell receptor (TCR) sequencing was performed on 93 pre- and post-treatment, multi-region tumour and peripheral blood samples from 15 patients. We showed that an increased Granzyme B production in the CD8 cells and higher B cell infiltration at baseline were associated with response to Nivolumab. TCR sequencing analysis showed that maintenance of expanded TCR clones during the anti-PD1 treatment which were present pre-treatment and increased clustering of TCR clonotypes are associated with response to therapy. Comparing a responder patient with a non-responder by using single cell RNA Sequencing (SC RNA Seq) showed a more dysfunctional phenotype in the responder. In addition, Nivolumab bound CD8 cells in the responder also had higher Granzyme B and TCF7 expression suggesting a more cytotoxic and progenitor-like phenotype is associated with response. This study provides important data that needs to be validated in a bigger cohort to identify biomarkers of response to anti-PD-1 therapy in ccRCC.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Deciphering the Immune Landscape in Renal Cell Carcinoma and in Anti-PD-1 Therapy |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10146680 |
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