A Researcher Live Series

Cancer Treatment Response in TIME

November-December 2022

#TIMECancer


The tumour immune microenvironment (TIME) plays a critical role in the evolution and progression of cancer. TIME is a highly complex and heterogeneous system that encompasses cells of the immune system and their interactions with the tumour microenvironment. The balance of suppressive versus cytotoxic responses in the tumour microenvironment is balanced by TIME and this can influence disease outcome, with high levels of T cell infiltration associated with better survival in patients. In this series, we explore the impact of TIME on response to cancer treatment and how certain treatments can alter the composition of the TIME and be used in combination with immunotherapy to improve patient outcomes.

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Programme

Topic

Date

B cells, tertiary lymphoid structures, and response to cancer immunotherapy

with Dr Florent Petitprez, University of Edinburgh

Wednesday, 30 November

10 am GMT

Investigating how radiotherapy affects the tumour immune microenvironment

with Dr Eleanor Cheadle,  University of Manchester

Wednesday, 7 December

10 am GMT

Stromal cells and immunosuppression in the tumour microenvironment

with Dr Aideen Ryan, University of Galway

Wednesday, 14 December

10 am GMT

 

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B cells, tertiary lymphoid structures, and response to cancer immunotherapy

with Dr Florent Petitprez, University of Edinburgh

Florent Petitprez

In recent decades, immunotherapies have revolutionised the treatment of cancer. However, only a minority of cancer patients respond to these therapies, and biomarkers to predict response are still scarce. To better understand this, we need to study the tumour microenvironment, a complex interconnected system that encompasses not only malignant cancer cells but also virtually any type of immune cell as well as fibroblasts and blood vessels.

Many studies show that the composition of the tumour microenvironment strongly associates with patients' survival and response to different therapies. The tumour microenvironment of some tumours can harbour lymphoid cell aggregates called tertiary lymphoid structures (TLS). These are lymph node-like groups of cells that can act as a site of activation and maturation of a potent anti-tumour immune response.

During this event, we will talk about how TLS and tumour-infiltrating B cells can be biomarkers for patient survival and response to immunotherapy in soft-tissue sarcoma and other solid tumours. We will also explain one of the mechanisms by which TLS favour anti-tumour immunity in kidney cancer by propagating anti-tumour plasma cells.

About the speaker

Florent Petitprez is a computational biologist interested in the tumour microenvironment of solid tumours. He obtained a PhD in immunology under the supervision of Professor Wolf Fridman at the Cordeliers Research Centre in Paris. His main work during his PhD was the demonstration that B cells and Tertiary Lymphoid Structures were associated with response to immunotherapy in soft-tissue sarcoma.

He is currently a postdoctoral research fellow at the MRC Centre for Reproductive Health, working with Professor Jeffrey Pollard on the phenotype and clinical impact of tumour-associated macrophages using spatial transcriptomic approaches. He recently obtained a Wellcome Trust Early Career Award to pursue his work on macrophages and tertiary lymphoid structures in cancer.


Investigating how radiotherapy affects the tumour immune microenvironment

with Dr Eleanor Cheadle,  University of Manchester

Eleanor Cheadle

Radiotherapy is given to around half of cancer patients as part of their treatment to directly shrink their tumours. There are occasions where radiotherapy given to one tumour lesion can lead to shrinkage of distant non-irradiated lesions but whilst these incidences of “abscopal effect” are clinically rare, it demonstrates that radiotherapy is able to prime systemic anti-tumour immunity. Furthermore, pre-clinical models show that radiotherapy can be immune-stimulatory with infiltration of T-cells into tumours. However, radiotherapy can also be immunosuppressive with, for example, increased numbers of suppressive myeloid cells infiltrating the tumour microenvironment.

The immune composition of the tumour microenvironment is prognostic in many cancer types with increased T cell infiltration associated with greater overall survival. The TME can also predict response to various immunotherapies such as immune checkpoint inhibitors and pre-clinical data shows that this is also the case for radiotherapy/ immunotherapy combination treatments. Our research investigates how radiotherapy alters immune cells' infiltration into the tumour and what effect it has on systemic immunity. We wish to identify biomarkers which can predict the immune effects of radiotherapy so that we can develop personalised radiotherapy/immunotherapy combination treatments to improve patient outcomes.

About the speaker

Dr Eleanor Cheadle undertook her PhD at the University of Leeds from 1999-2002, studying recombinant mycobacterial cancer vaccines and their interaction with dendritic cells and lymphocytes under the supervision of Dr Andrew Jackson and Professor Peter Selby. She then moved to the University of Manchester in 2002 where she began work as a postdoctoral research associate in the group of Professor Robert Hawkins and Dr David Gilham. Her work focused on the generation and testing of chimeric antigen receptor (CAR) T-cells targeting CD19 for use in the treatment of B-cell malignancies. This work led to an ongoing Kay Kendall Leukaemia-funded Phase I clinical trial testing CD19 CAR T-cells in B-cell lymphoma.

In 2009 she joined the Targeted Therapy group led by Professor Tim Illidge, and her research has focused on investigating the mechanisms of action of type I and type II anti-CD20 antibodies and improving their efficacy in B-cell malignancies through the use of immunomodulatory agents to enhance adaptive immune responses. In 2018 she took an NIHR BRC-funded post to lead translational science within the Targeted Therapy Group to investigate dynamic immune biomarkers of response to radiotherapy in the tumour microenvironment and systemic circulation.


Stromal cells and immunosuppression in the tumour microenvironment

with Dr Aideen Ryan, University of Galway

Aideen Ryan1

The motivation behind our research arises from the limited efficacy of immunotherapies in stromal-dense tumour microenvironments (TME). T cell-based immunotherapies, including immune checkpoint inhibitors and CAR T cell therapies, are approved backbone therapies for many blood cancers and some solid malignancies. However, T cell-based immunotherapies in solid stromal-dense tumours such as pancreatic, multiple myeloma and colorectal cancers have shown only limited success indicating that their optimization requires a deeper understanding of the immunosuppressive mechanisms that dominate these tumour landscapes. 

Stromal cells, including mesenchymal stromal cells and cancer-associated fibroblasts, sense and switch inflammation to maintain homeostasis in the body. In the TME, they are recognized as a major obstacle for immunotherapies as they play a key role in immune suppression; however, the mechanisms underlying this are not fully understood. 

In this presentation, I will summarise some of our recent findings where we identify novel mechanisms of immunosuppression; including stromal cell immune checkpoints and sialic acid – single interactions that can result in immune cell dysfunction. This knowledge may pave the way for the development of more efficient stromal cell-targeted immunotherapies for the treatment of cancer. Using representative models of tumours that arise in stromal-dense microenvironments, we demonstrate that tumour-induced stromal cells can dictate anti-tumour immune responses and may represent a therapeutic target in cancer. 

About the speaker

Dr Aideen Ryan is an Associate Professor in Tumour Immunology in the School of Medicine, Discipline of Pharmacology & Therapeutics at NUI Galway. She graduated with a bachelor’s degree in Biochemistry from NUI Galway in 2001 and a PhD in Medicine from the University College Cork in 2006. She completed her postdoctoral training in the labs of Prof. Laurence Egan, and Prof Thomas Ritter at NUI Galway before starting her independent research group at NUI Galway in 2017.

Aideen’s research team are uncovering novel stromal cell targets that shape the immunosuppressive microenvironment in cancer. Aideen’s research is published in high-ranking journals and has led to several recent prestigious independent grants, postdoctoral fellowships and international awards including a Top Outstanding Young Peoples Award, Future Leaders Award (SITC, USA), Irish Cancer Society Research Paper of the Year award, NUI Presidents Award for Research Excellence, SFI Starting Investigator Research Award.

Aideen is a named inventor on patents relating to discoveries on novel mechanisms to activate the immune system in cancer to enhance immunotherapy. As part of a visiting senior lectureship at Bart’s Cancer Institute, QMUL, London, Aideen’s group are developing 3D models, in collaboration with Prof Fran Balkwill and Dr Daniela Loessner, to investigate mechanisms of immune evasion in colon cancer with a particular focus on the influence macrophage/stromal cell interactions on anti-tumour immunity. Her research aims to uncover new stromal cell therapeutic targets to overcome immunosuppression in cancers to optimise and increase response to immunotherapies.