Abstract
Simple SummaryTargeting tumour-specific defects in the DNA damage response (DDR) presents an opportunity for new therapeutic approaches to selectively kill cancer cells. Although the therapeutic rationale of DDR-targeted agents initially focused on their actions against tumour cells, these agents might also alter the crosstalk between tumour cells and the immune system. Here, we discuss recent data showing that DDR-targeted agents affect the antitumour immune response both through direct actions on the immune system components and through indirect effects on expression of different molecules and pathways in tumour cells that underpin the tumour cell–immune system.The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression. In this review, we summarise recent data on how DDR-targeted agents can affect the interactions between tumour cells and the components of the immune system, both by acting directly on the immune cells themselves and by altering the expression of different molecules and pathways in tumour cells that are critical for their relationship with the immune system. Obtaining an in-depth understanding of the mechanisms behind how DDR-targeted therapies affect the immune system, and their crosstalk with tumour cells, may provide invaluable clues for the rational development of new therapeutic strategies in cancer.
Highlights
The genome is exposed to a multitude of genotoxic insults, both exogenous and endogenous, that generate DNA damage
Aberrations in the DNA damage response (DDR) result in genomic instability, which is a hallmark of cancer cells but at the same time opens up cancer treatment opportunities by targeting tumour-specific DDR defects to selectively kill cancer cells [2]
The approval of Poly(ADP-ribose) polymerases inhibitors (PARPi) for clinical use in different tumour types has highlighted the usefulness of targeting DDR components for cancer treatment
Summary
The genome is exposed to a multitude of genotoxic insults, both exogenous (e.g., mutagenic chemicals, ionising radiation) and endogenous (e.g., reactive oxygen species), that generate DNA damage. Concomitant to DNA break repair, a rapid signalling cascade must be coordinated at the lesion site, which leads to activation of cytostatic and cytotoxic responses that limit the expansion of the damaged cells. These mechanisms are referred to as the DNA damage response (DDR) [1]. These DDR-targeting agents have mainly been considered for their intrinsic actions towards tumour cells per se. Understanding how DDR-targeted therapies affect (i) the immune system and (ii) the crosstalk between the immune system and tumour cells may provide invaluable clues for designing new (and refining existing) therapeutic strategies in cancer
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