Immunological consequences of chemotherapy: implications for cancer immunotherapy

Despite the success of immunotherapy, chemotherapy remains the backbone of front-line therapy for most patients with cancer. Immune checkpoint inhibitors, T cell engagers, and adoptive cell therapies have traditionally been relegated to second-line or later settings. However, accumulating evidence of improved clinical responses when immunotherapy is administered to less heavily pretreated patients has prompted the incorporation of these modalities earlier in treatment scheduling. Yet, mechanistic understanding of factors driving improved immunotherapy response rates among less heavily pretreated patients remains limited. Decades of study have established that systemic chemotherapy produces immunomodulatory effects, fundamentally altering the immune landscape. Chemotherapy transiently modulates the tumor immune microenvironment to support antitumor immune responses through several mechanisms, including depletion of immunosuppressive cells and induction of immunogenic cell death. However, chemotherapy exposure is also associated with lasting deleterious effects on cells of the immune system, promoting clonal hematopoiesis, cellular aging, and senescence through a variety of molecular mechanisms. Importantly, lasting chemotherapy-induced changes can persist in immune cells of patients with cancer and survivors for several years following chemotherapy exposure, making them susceptible to secondary malignancies. Evidence of lasting damage to the immune system raises important questions regarding how prior chemotherapy exposure ultimately influences the efficacy of immunotherapy. In this review, we provide an overview of the consequences of chemotherapy on the cells of the immune system, with particular focus on the long-term deleterious effects of chemotherapy exposure, translational implications for modern immunotherapy, and potential strategies to overcome or circumvent chemotherapy-induced cellular damage.