Immunological and genetic association with Cancer development- V1
Research type
Research Study
Full title
Immunological and genetic association of virus/pathogen linked with cancer development
IRAS ID
212753
Contact name
Tao Dong
Contact email
Sponsor organisation
University of Oxford
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
IImmunotherapy aimed at improving tumour antigen-specific immune responses and is considered a promising treatment approach, in particular for pathogen associated cancers. In recent years, multiple inhibitory receptors (known as immune checkpoint receptors), expressed on T cells, have been identified. Recent exiting results from clinical trials with antibodies targeting these inhibitory receptors, such as PD-1 and CTLA4, have demonstrated their ability to activate anti-tumour immunity in a broad range of cancer patients, with dramatic therapeutic results. Successful application of this novel immunotherapeutic approach in cancer patients will have to take into account the cancer-specific immune microenvironment that underlies the cancer development and that could influence the response to treatment. However, little is known about the effect of virus infection on cancer microenvironment and their effect on differentiating cancer-specific T cells during cancerdevelopment. For instance, it is not known whether the cancer microenvironment modulates the expression pattern of immune checkpoint inhibitors on cancer-specific T cells. Careful characterization of the phenotype and functionality of viral and cancer-specific T cells will provide insights into the mechanisms by which virus infection hampers cancer-specific T cells and will lead to therapeutic opportunities. The hypothesis which we are therefore setting out to test is that the quality of cancer-specific T cells can be modulated by the tumour micro-environment and the presence or absence of chronic infection by virus.
Lay summary of study results:
Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects.
We initiated our study by examining the ex vivo expression levels of eight well-known immune checkpoint receptors on tumor-infiltrating T cells (TILs) and matched circulating T cells in the bloodstream, employing flow cytometry. Our analysis revealed an upregulation of PD-1 and Tim-3 expression on TILs, contrasting with a downregulation of BTLA expression when compared to peripheral blood samples from various cancer types. This data highlights the potential efficacy of targeting PD-1 and Tim-3 as effective candidates for immune checkpoint blockade. On the other hand, the Group 2 immune checkpoint receptors, including BTLA, may hold diminished significance in checkpoint blockade due to their higher expression on peripheral T cells, which could potentially lead to immune-related adverse effects.
We further conducted an in-depth examination of immune checkpoint receptors on CD8+ Tumor Infiltrating Lymphocytes in cervical cancer patients. Our investigation uncovered a significant association between high PD-1 expression and unfavorable overall survival among cervical cancer patients. Moreover, the CD8+/CD4+ TIL ratio and the presence of HPV infection emerged as risk factors for early relapse and mortality in these patients. These discoveries hold crucial implications for predicting cervical cancer relapse through cellular diagnostics and are valuable insights for selecting potential candidates for PD-1 blockade therapy.REC name
London - City & East Research Ethics Committee
REC reference
16/LO/1607
Date of REC Opinion
7 Oct 2016
REC opinion
Further Information Favourable Opinion