Acquired Resistance to Immune Checkpoint Inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.

Keywords: ICIs; acquired resistance; immunotherapy.

Figure 1.. Rate of acquired resistance and overall response by tumor type.

Different tumor types are represented by colored circle and number of patients is represented by size of the circle.

Figure 2.. Summary of reported mechanisms of acquired resistance to immune checkpoint inhibitors.

The number of clinical cases by reported mechanism of acquired resistance mechanism are shown. Some cases report multiple acquired resistance mechanisms.

Figure 3.. Schema of interaction between T cell and tumor cells, highlighting loci for proposed mechanisms of acquired resistance to immune checkpoint inhibitors.

Central cartoon depicts engagement between T cell (green) and tumor cell (blue). Transmembrane-bound T-cell receptor (TCR) and PD-1 receptor are depicted along T cell membrane, along with elaboration of IFN-γ cytokine granules into the extracellular space. Along the tumor cell membrane are the transmembrane-bound peptide-MHC class I receptor, stabilized by B2M, PD-L1 ligand, and IFNGR1/IFNGR2 heterodimer, bound by JAK1 and JAK2. Downstream of JAK1/JAK2 activates phospho-STAT, which engages with tumor cell DNA to regulate, among other targets, MHC-I and PD-L1 expression. Surrounding inset figures depict individual postulated mechanisms of acquired resistance that modulate or interfere with the normal engagement between a T cell and tumor cell. (A) Disruption/downregulation of antigen presentation machinery: Mutations or loss of MHC-I or B2M lead to loss of tumor antigen presentation and lack of TCR engagement. (B) Loss of IFN-γ sensitivity: mutations or loss of IFNGR1/IFNGR2 or JAK1/2 lead to insensitivity to IFN-γ in tumor microenvironment and resistance to anti-PD-1 mediated T cell response. (C) Neoantigen depletion: A clonally heterogenous tumor (blue, green, and purple circles) is affected by selective pressure from effective response to anti-PD-1 blockade, leading to loss of clones containing effective neoantigens (with blue circles lost post-treatment). Cartoon below depicts peptide-MHC-B2M complex with neoantigen epitope in pre-treatment setting, which is then lost post-treatment. (D) Tumor-mediated immunosuppression/exclusion: upregulated WNT signaling leads to stabilization of β-catenin or PTEN mutations/loss can ultimately yield immune-suppressive and -exclusionary cytokines that reduce infiltration and function of CD8+ T cells in the tumor microenvironment. (E) Additional inhibitory checkpoints: upregulation of additional immune checkpoints such as TIM3, LAG3, and VISTA can be found at the time of acquired resistance, and may reflect terminal exhaustion and fixed loss of effector function.