Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

Abstract

Cancer patients with low or absent pre-existing anti-tumour immunity ("cold" tumours) respond poorly to treatment with immune checkpoint inhibitors (ICPI). In order to render these patients susceptible to ICPI, initiation of de novo tumour-targeted immune responses is required. This involves triggering of inflammatory signalling, innate immune activation including recruitment and stimulation of dendritic cells (DCs), and ultimately priming of tumour-specific T cells. The ability of tumour localised therapies to trigger these pathways and act as in situ tumour vaccines is being increasingly explored, with the aspiration of developing combination strategies with ICPI that could generate long-lasting responses. In this effort, it is crucial to consider how therapy-induced changes in the tumour microenvironment (TME) act both as immune stimulants but also, in some cases, exacerbate immune resistance mechanisms. Increasingly refined immune monitoring in pre-clinical studies and analysis of on-treatment biopsies from clinical trials have provided insight into therapy-induced biomarkers of response, as well as actionable targets for optimal synergy between localised therapies and ICB. Here, we review studies on the immunomodulatory effects of novel and experimental localised therapies, as well as the re-evaluation of established therapies, such as radiotherapy, as immune adjuvants with a focus on ICPI combinations.

Keywords: immune checkpoint inhibitors; immunosuppression; oncolytic virus; radiotherapy; tumor microenvionment.

Figure 1

Immunologically “cold” tumours are generally unresponsive to ICPI and characterised by low infiltration and/or exclusion of cytotoxic lymphocytes, including CD8 T cells and NK cells. Further, cold tumours often have high infiltration of immunosuppressive cells including Tregs, CAFs, and M2-polarized macrophages as well as low expression and presentation of tumour neoantigens preventing priming of de novo immune responses. Immunogenic localised therapies are designed to convert ‘cold’ tumours to a ‘hot’ by altering the adjuvanticity and antigenicity of the TME. Antigenicity is achieved by augmented expression, degradation and presentation of tumour neoantigens while adjuvanticity is associated with elevated levels of DAMPs, released from dying tumour cells, cytosolic DNA accumulation and sensing, and a transcriptional profile geared towards IFN type I signalling. Together, these factors promote recruitment, infiltration and activation of DCs allowing for increased antigen cross-presentation and priming of tumor-specific CD8 T cells. Triggering of these events by localised therapies creates a favourable environment for synergy with ICPI. The pool of activated cross-presenting DCs cooperates with anti-CTLA-4 treatment to generate a broadened repertoire of tumour neoantigen-specific T cells whose effector function can be augmented by anti-PD-1 treatment in their killing of tumour cells locally and systemically. TME, tumour microenvironment; DAMP, danger-associated molecular pattern; DC, dendritic cell; CAF, cancer-associated fibroblast; ICPI, immune checkpoint inhibitor; NK cell, natural killer cell.