The Host Response To Immune Checkpoint Inhibitors: From Mechanisms To Therapeutic Implications.

e14584 Background: One of the major challenges in clinical immuno-oncology today is predicting which patients will respond to treatment. Although the use of immune checkpoint inhibitors (ICIs) has significantly improved therapeutic outcomes in a subset of patients with advanced malignancies, the majority of patients do not respond to treatment and some even hyper-progress. This response pattern raises questions regarding the possible mechanisms of resistance to ICIs. In the last decade we and others have shown that the host, in response to almost any type of anti-cancer drug, generates pro-tumorigenic and pro-metastatic effects which in turn contribute to tumor relapse and resistance to therapy despite an initial response. However, such host effects have never been investigated using immune-oncology drugs. Methods: We used functional and computational methods on plasma samples from both mouse models and cancer patients to identify the host-mediated tumor promoting molecular pathways that are induced in response to ICI therapy. Results: We found that these pathways are composed of dominant factors that regulate pro-inflammatory, metastatic and proliferation activities and thus contribute to rapid tumor re-growth. In pre-clinical models, we have found that pharmacological blockade of specific dominant factors overcomes the tumor-promoting effects induced by the host in response to ICI therapy. Conclusions: Based on our collective findings, we propose that therapies inhibiting host-mediated pro-tumorigenic effects could be used in combination with ICIs as a strategy to minimize tumor hyper-progression and increase the susceptibility of resistant tumors to ICI therapy. Furthermore, our studies pave the way towards the discovery of new predictive biomarkers for identifying subjects who will benefit from ICI therapy.