Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

Abstract

Immune checkpoint blockade (ICB) has rapidly transformed the treatment paradigm for various cancer types. Multiple single or combinations of ICB treatments have been approved by the US Food and Drug Administration, providing more options for patients with advanced cancer. However, most patients could not benefit from these immunotherapies due to primary and acquired drug resistance. Thus, a better understanding of the mechanisms of ICB resistance is urgently needed to improve clinical outcomes. Here, we focused on the changes in the biological functions of CD8+ T cells to elucidate the underlying resistance mechanisms of ICB therapies and summarized the advanced coping strategies to increase ICB efficacy. Combinational ICB approaches and individualized immunotherapies require further in-depth investigation to facilitate longer-lasting efficacy and a more excellent safety of ICB in a broader range of patients.

Programmed Cell Death-Ligand 1 in Head and Neck Squamous Cell Carcinoma: Molecular Insights, Preclinical and Clinical Data, and Therapies

“…In most cases, the increase in membrane PD-L1 levels gives cancer cells an advantage in evading immune defenses. But when these subjects are treated with immunotherapy at higher levels of PD-L1, there is also a greater susceptibility to drugs [ 2 ] as observed for other types of cancer [ 45 , 46 , 47 ].…”

Prospects and feasibility of synergistic therapy with radiotherapy, immunotherapy, and DNA methyltransferase inhibitors in non-small cell lung cancer

“…Although a few patients have achieved significantly longer survival, most patients would have treatment failure due to primary or acquired treatment resistance (65,66). From tumor-specific antigens recognition to cross-presentation, from T cell activation to recruitment, ICIs treatment resistance occurs at every step of the tumor immune cycle (67). The causes of ICIs treatment resistance include tumor-intrinsic and tumor-extrinsic mechanisms.…”

Tissue biomarkers of immune checkpoint inhibitor therapy

“…3,4 Immune checkpoint inhibitors (ICIs), including monoclonal antibodies and small molecule inhibitors, are a type of immunotherapy designed to disrupt the interaction of ICs with their ligands. 5,6 Because of its durability in response and improved patient survival, ICI therapy has become a promising and effective treatment approach. 7 As ICI therapies continue to demonstrate their effectiveness in patients with advanced-stage cancer, there is a rising interest in exploring their potential for earlier-stage disease.…”

“…The interaction of programmed cell death protein 1 (PD‐1) protein on immune cells with its ligand programmed death ligand 1 (PD‐L1) presented on tumor cells triggers PD‐1/PD‐L1 signaling that hampers further immune activation, enabling evasion of antigen‐specific T‐cell responses 3,4 . Immune checkpoint inhibitors (ICIs), including monoclonal antibodies and small molecule inhibitors, are a type of immunotherapy designed to disrupt the interaction of ICs with their ligands 5,6 . Because of its durability in response and improved patient survival, ICI therapy has become a promising and effective treatment approach 7 .…”