Abstract
The interaction between programmed cell death protein (PD-1) and its ligand (PD-L1) is one of the main pathways used by some tumors to escape the immune response. In recent years, immunotherapies based on the use of antibodies against PD-1/PD-L1 have been postulated as a great promise for cancer treatment, increasing total survival compared to standard therapy in different tumors. Despite the hopefulness of these results, a significant percentage of patients do not respond to such therapy or will end up evolving toward a progressive disease. Besides their role in PD-L1 expression, altered protein kinases in tumor cells can limit the effectiveness of PD-1/PD-L1 blocking therapies at different levels. In this review, we describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments.
Highlights
BackgroundGiven their ability to destroy aberrant cells, such as pathogen-infected cells or cancer cells, T-cells play a key role in cell-mediated immunity
We describe the role of kinases that appear most frequently altered in tumor cells and that can be an impediment for the success of immunotherapies as well as the potential utility of protein kinase inhibitors to enhance the response to such treatments
Kirsten rat sarcoma viral oncogene (KRAS) involvement in pathways related to both apoptosis inhibition and PD-L1 overexpression turn this oncogene into a potential prognosis marker that should be considered when stratifying patients for immunotherapy, as it has been already reported in patients with lung adenocarcinomas with KRAS mutations [116] and the rational use of kinase inhibitors targeting PI3K/AKT and MAP kinases in candidate patients for immunotherapy with KRAS mutant tumors should be considered
Summary
Given their ability to destroy aberrant cells, such as pathogen-infected cells or cancer cells, T-cells play a key role in cell-mediated immunity. T-cells survival, which dramatically affects T-cell activation and cytokine production, and T-cell capacity to repress tumor cells This interaction is essential to maintain homeostasis of the immune response to prevent autoimmunity during infection or inflammation of normal tissues, in tumor microenvironments it provokes an immune escape for tumor cells through cytotoxic T-cell inactivation. Resistance to anti-PD-1/PD-L1 therapy is present in up to 70% of patients [8], with up to 60% of patients presenting a primary resistance [8,9], which can be responsible for disease progression or relapse [4] and stresses the need to continue investigating for response biomarkers crucial for patient selection Recent studies in this field have proposed different biomarkers as tools to predict the efficacy of PD-1/PD-L1 inhibitors [10] (Table 1).
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