Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies

Abstract

The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly with the advent of immune checkpoint inhibitors. However, many patients do not derive benefit from checkpoint blockade, developing either primary or secondary resistance, highlighting a need for alternative approaches to modulate immune function. In this review, we highlight the absence of a common definition of primary and secondary resistance and summarize their frequency and clinical characteristics. Furthermore, we provide an overview of the biomarkers and mechanisms of resistance involving the tumor, the tumor microenvironment and the host, and suggest treatment strategies to overcome these mechanisms and improve clinical outcomes.

Keywords: PD-L1; acquired resistance; immune checkpoint inhibitors; primary resistance.

Figure 1.

A spider plot representing examples of resistance to immune checkpoint inhibition with (P) primary resistance, defined as best response being disease progression; (AR1) acquired resistance, defined as initial stable disease and subsequent disease progression; and (AR2) acquired resistance, defined as initial response and subsequent disease progression.

Figure 2.

Biomarkers of primary and acquired resistance occurring in the (A) tumor microenvironment (TME), (B) in the tumor, and (C) host factors. Within the TME, factors involved in primary resistance (blue font) includes the presence of (a) immunosuppressive cells including cancer associated fibroblasts (CAFs), myeloid derived suppressor cells (MDSCs), regulatory T cells (T reg), M2 macrophages, and reduced tumor infiltrating lymphocytes (TILs), (b) immune-suppressive molecules such as indoleamine 2,3-dioxygenase (IDO), adenosine, vascular endothelial growth factor (VEGF), glucose, and (c) tumoral factors such as reduced PD-L1 expression, tumor mutation burden (TMB), intra-tumoral heterogeneity (ITH), genetic loss of HLA class I, dysregulated IFN/JAK pathway, aberrant oncologic signaling pathways (PTEN loss, mutations in WNT/b-catenin, LKB1, c-myc). Biomarkers associated with acquired resistance (red font) include (d) loss of B2m and MHC-I, neoantigen evolution with loss of neoepitopes; the IFN/JAK escape pathway with loss of function JAK-1 and JAK-2 mutations and (e) the upregulation of other immune checkpoints such as T-cell immunoglobulin, mucin domain-3 protein (TIM-3), lymphocyte-activation gene 3 (LAG-3), B and T lymphocyte attenuator (BTLA), T-cell immunoreceptor tyrosine-based inhibition motif domain (TIGIT), and V-domain immunoglobulin-containing suppressor of T-cell activation (VISTA). Host factors affecting resistance includes (e) gut microbiome and antibiotic use.