Molecular determinants governing CD8+ T cell mediated anti-tumor immunity

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Version: After imprimatur
Serval ID
serval:BIB_08CEE3B79D75
Type
PhD thesis: a PhD thesis.
Collection
Publications
Institution
Title
Molecular determinants governing CD8+ T cell mediated anti-tumor immunity
Author(s)
Martinez-Usatorre Amaia
Director(s)
Romero Pedro
Codirector(s)
Donda Alena
Institution details
Université de Lausanne, Faculté de biologie et médecine
Address
Département d'oncologie fondamentale
Biopole 3
Ch. des Boveresses 155
CH-1066 Epalinges
Publication state
Accepted
Issued date
27/04/2018
Language
english
Number of pages
117
Abstract
Despite the ability of CD8+ T-cells to recognize and kill cancer cells, tumors manage to evade immune control through multiple mechanisms. Immunotherapeutic strategies have shown clinical benefit in some but not all cancer types or patients. Hence, a better understanding of the key parameters governing the complex relationship between CD8+ T-cells and tumors is necessary to ensure the success of immunotherapy in most cancer patients.
Anti-tumor T-cell responses mostly involve CD8+ T-cells with high affinity for mutated self-antigens and of low affinity for tumor-associated antigens. Therefore, the first part of my thesis project addressed the impact of the recognition strength between the TCR and its antigen in CD8+ T-cell mediated anti-tumor responses. We found that CD8+ T-cell peripheral priming with a high affinity peptide vaccine was necessary to control low affinity antigen expressing B16 melanoma tumors. In addition, despite a high affinity peripheral priming, the affinity for the antigen that CD8+ T-cells encountered later in the tumor influenced on the CD8+ T-cell response: low affinity antigen recognition led to decreased CD8+ T-cell expansion and tumor control while induced lower expression levels of inhibitory receptors and increased cytokine production upon ex vivo restimulation. Interestingly, tumor infiltrating CD8+ T-cells regardless of their affinity for the tumor antigen, responded equally to PD-1 blocking monoclonal antibodies. Moreover, when tumor infiltrating CD8+ T-cells were re-transferred to tumor-free hosts, they showed similar in vivo re-expansion capacity irrespectively of the affinity for the tumor antigen. Interestingly, the re-expansion capacity of these T-cells was similar to that of their counterparts isolated from secondary lymphoid organs, suggesting that CD8+ T-cells in tumors may be rekindled upon relief of tumor immunosuppression.
Our group had previously shown the importance of micro-RNA-155 (miR-155) for CD8+ T cells anti-tumor responses, as its overexpression enhanced tumor control by CD8+ T cells. However, the quantitative aspects of the regulation of miR-155 expression levels were poorly characterized. Thus, the second part of my thesis addressed miR-155 expression regulation in mouse and human CD8+ T cells from healthy tissues and melanoma tumors. I demonstrated that T cell affinity and antigen dose are two important factors determining miR-155 expression levels in CD8+ T cells. Interestingly, high miR-155 expression levels correlated with increased tumor control in low affinity antigen expressing B16 tumors and anti-PD-1 treatment increased CD8+ T cells miR-155 expression levels. Moreover, CD8+ T cells overexpressing miR-155 showed enhanced persistence in chronic infections. In line with these observations in mouse model systems, miR-155 expression levels in human effector memory CD8+ T cells positively correlated with their frequencies in tumor infiltrated lymph nodes. Thus, we propose that miR-155 expression levels reflect responsiveness and affinity for the antigen and may be used as an overall marker of tumor infiltrating CD8+ T cells fitness.
Altogether, we suggest that combination of high affinity peripheral priming by altered peptide ligands and checkpoint blockade may enable tumor control of even low affinity antigen expressing tumors, which can be revealed by miR-155 upregulation in tumor infiltrating CD8+ T cells.

Keywords
CD8+ T cell, melanoma, affinity, microRNA-155, immunotherapy
Create date
01/05/2018 16:14
Last modification date
20/08/2019 13:31
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