Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies
Elisabeth Pérez-Ruiz 1 , Ignacio Melero 2 , Joanna Kopecka 3 , Ana Bela Sarmento-Ribeiro 4 , Marilina García-Aranda 5 , Javier De Las Rivas 6
(1) Medical Oncology Department, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Costa del Sol, 29603 Marbella, Malaga, Spain.
(2) Immunology and Immunotherapy Department, Clinica Universidad de Navarra (CUN), Center for Applied Medical Research (CIMA), Universidad de Navarra (UNAV), 31008 Pamplona, Spain.
(3) Department of Oncology, Turin School of Medicine, University of Turin, 10126 Turin, Italy.
(4) Laboratory of Oncobiology and Hematology and University Clinic of Hematology and Coimbra Institute for Clinical and Biomedical Research - Group of Environment Genetics and Oncobiology (iCBR/CIMAGO), Faculty of Medicine, University of Coimbra (FMUC), and Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal.
(5) Research Unit, Hospital Costa del Sol, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC) and Instituto de Investigación Biomédica de Málaga (IBIMA), 29603 Marbella, Malaga, Spain.
(6) Cancer Research Center (CiC-IBMCC, CSIC/USAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), and Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain.
Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases.
However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer.
While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host.
Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed.
Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3γ or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance.
This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance.
CITA DEL ARTÍCULO Drug Resist Updat . 2020 Jul 15;53:100718.