Role of immunosuppressive cells and immune checkpoints in the development and progression of colorectal and breast cancers

Abstract

The tumour microenvironment (TME) nurtures a tolerant microenvironment consisting of various immunosuppressive factors, which thwart potent anti-tumour immune responses to favour tumour progression and hinder response to therapy. Tumour progression is dependent on the balance between anti- and pro-tumour factors within the TME and can be facilitated by infiltration of leukocytes, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), which release various immunosuppressive factors and express inhibitory signals for T cell activation called immune checkpoints (ICs). Moreover, tumour cells exploit IC pathways via interactions between inhibitory IC molecules on tumour-resident T cells and IC ligands secreted by tumour cells/antigen presenting cells; these are recurrently upregulated in the TME of various malignancies to attenuate T cell responses. As presented in the set of works here, we performed comprehensive investigations on the immune constituents of the TME of colorectal cancer (CRC) and breast cancer (BC) tissues in order to decipher their roles in tumour progression. Flow cytometric analysis was performed on peripheral blood samples and tumour tissue, as well as paired adjacent, non-tumour samples, from CRC and BC patients to enable comprehensive phenotypic characterization of myeloid cells and investigate IC and Treg-related marker expression in both the periphery and TME. We found high IC expression and accumulation of highly immunosuppressive MDSCs and Tregs in CRC and BC TME, with varying prognostic significance. Moreover, we also reported that pharmacological IC blockade did not affect Treg phenotype or function. Furthermore, we performed transcriptomic profiling of tumour-infiltrating myeloid cells from CRC patients with varying disease stages and identified a unique gene signature which could be used as an independent prognostic indicator for survival in CRC patients. Overall, this work has provided important insights into the immunosuppressive factors at play within the TME in both CRC and BC, which can guide and refine therapeutic targeting approaches for these cancers.

Date of Award	Aug 2021
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Sassan Hafizi (Supervisor)