Resistance to immune checkpoint inhibitors. Next steps and combinational approaches

Abstract

Immuno-oncology and in particular checkpoint inhibitor (CPI) treatment has become a novel promising cancer therapy strategy in recent years. However, still a minority of patients respond to checkpoint blockade. Primary and secondary resistance to CPI is a challenge in the daily clinical routine. Combination strategies have been tested in various clinical trials in order to address this issue. Data available from these trials indicate improved activity depending on the tumor type. This review article focuses on the molecular background for resistance to CPI, gives an overview of current clinical data of CPI combination studies and points out potential strategies to overcome CPI resistance depending on the immune phenotype.

Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy

“…Here, the role of Tregs, myeloid-derived suppressor cells (MDSCs) and type II macrophages is highlighted, as well as that of regulatory molecules released in the TME, such as IFN-γ, IDO, CEACAM1, TIM-3, TGF-β or adenosine [ 80 , 86 ]. Other host factors that also influence treatment resistance include endocrine, metabolic, environmental (dysbiosis, antibiotic or steroid consumption) and personal factors (age, chronic disease or genetic susceptibility) [ 87 ]. Additionally, different resistance mechanisms (primary/secondary) and antitumor immunity converge depending on the tumor phenotype.…”

“…Immunoexcluded tumors are able to evade stromal factors as a result of mechanical barriers, vascular factors or an immune-suppressive chemokine state. In the case of immunoinflammed tumors, all the mechanisms mentioned above come together [ 87 ]. In addition, Syn et al [ 88 ] observed a parallelism between the primary and secondary resistance mechanisms.…”

“…This has been shown in lung cancer, where PD-L2 and FASL are enriched within the stromal regions of tumors [ 106 ]. TGF-β can also be secreted, as well as other inhibitory cytokines such as IL-10 or IL-35, by Treg cells to prevent the immune response within the lung tumor environment [ 87 ] by inducing CD4 + T-cell differentiation into inducible Tregs (iTregs) [ 102 ].…”

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

“…Resistance to immunotherapy can be classified as primary (or innate) and secondary or acquired [12][13][14][15]. Some authors also refer to an intermediate phenotype that is adaptive resistance [16].…”

Overcoming resistance and bypassing checkpoints—possible new therapeutic frontiers in oncology

“…Wieser et al [3] discuss novel approaches as PARP (poly ADP ribose polymerase) inhibition and forecast that therapy may require different approaches depending on the molecularly defined subgroups of OC ("differentiated", "immunoreactive", "mesenchymal" and "proliferative"). Furthermore, Fuereder [4] gives an overview on immunotherapy resistance and focuses on the molecular background of resistance to checkpoint inhibition (CPI) and outlines current clinical data of CPI combination studies. Future potential strategies to overcome CPI resistance might also depend on the immune phenotype.…”