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.

Innate lymphoid cells recruit T cells to turn up the heat on tumors

“…However, ICI-based therapies are only effective in a proportion of patients in a relatively small range of cancer. Certain tumors, termed ''cold tumors'' because they lack infiltrating T cells, resist the effects of ICI, whereas ''hot tumors,'' which have significant tumor-infiltrating T cells, respond to ICI therapy (Appleton et al, 2021).…”

Immunosuppressive tumor microenvironment in extraskeletal myxoid chondrosarcoma: A case of pleural metastases

“…Low tumor mutational burden and few pathogenic variants may lead to low tumor antigenicity, causing the decreased recruitment of CD8 + T cells into the tumors. 12 The present study has several limitations. First, the discrepancy of infiltration between M2 macrophages and regulatory T cells was observed.…”

Targeting tumor microenvironment for cholangiocarcinoma: Opportunities for precision medicine

“…The classification in four immune subtypes proposed by Job and colleagues provides several suggestions for treatment and study design [10] . For example, in the “immune desert subtype”, strategies aiming to convert “cold” tumors into inflamed tumors, such as the association of ICIs with local therapies or with agents targeting cellular DNA damage repair, could represent a promising approach [ 94 ]. The “immunogenic subtype” would probably benefit from ICIs, as its TME presents immune-stimulating factors, suggesting an effective anticancer immune response.…”