Immune modulation of cancer: mechanisms and resistance
The development and clinical application of immune modulation represent one of the most extraordinary achievements in the treatment of cancer. Monoclonal antibodies against checkpoint inhibitors are actually used in clinical practice, but other antibodies that stimulate co-accessory molecules or kill regulatory cells are being studied. Interestingly, some conventional chemotherapeutics and tyrosine kinase inhibitors not only kill cancer cells but also modulate the immune response against tumors in that the induced immunogenic cell death can modulate tumor microenvironment (TME) cells. However, the tumor can hijack response to treatment and can be helped by the tolerogenic nature of the TME, resulting in an unexpected resistance that allows tumor progression in many patients.
In this review, after presenting how immune cells in TME are modulated by anticancer treatments, we analyze the mechanisms responsible for primary and secondary resistance to immunomodulatory drugs highlighting the urgent need to discover ways to overcome resistance. One such way is the association of drugs that modulate the activity of immune cells in the TME, particularly when they stimulate the immune system through different mechanisms.
The most promising approach to overcome drug resistance in cancer is the combination of treatments performed both in a biomarker-selected mode and as a first-line treatment.