The dual role of inflammation in cancer immunity

Immunotherapies based on antibodies that target T cell-immune checkpoints have transformed the landscape of cancer treatment across multiple tumour types. These therapies can promote long-lasting responses in both patients with late-stage cancers or in (neo)adjuvant settings. However, most patients derive only transient or no benefit, and many face harmful side effects. Solutions to these clinical problems require improved fundamental understanding of the principles that govern anti-cancer immune responses. Our group at the Cancer Research UK Manchester Institute investigates the signals and pathways that dictate the establishment of tumour inflammatory environments that promote or restrain the anti-tumour function of the immune system. Combining the use of genetically engineered pre-clinical models with the analysis of cancer patient samples, we aim to identify the underlying mechanism that allow immune escape and enable progressive tumour growth and spread. In doing so, we have identified the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway as a nodal inflammatory axis that drives immune evasion and therapy resistance. Of therapeutical relevance, we showed that pharmacological inhibition of the COX-2/PGE2 pathway with widely use anti-inflammatory drugs represents a promising approach to augment the efficacy of immunotherapy and chemoimmunotherapy combinations. Collectively, our data uncovers the COX-2/PGE2 axis as a bona fide immune checkpoint that can be readily targeted to enhance the efficacy of immune-based cancer treatments.