Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance

Abstract

Recent advances in the understating of tumor immunology suggest that cancer immunotherapy is an effective treatment against various types of cancer. In particular, the remarkable successes of immune checkpoint-blocking antibodies in clinical settings have encouraged researchers to focus on developing other various immunologic strategies to combat cancer. However, such immunotherapies still face difficulties in controlling malignancy in many patients due to the heterogeneity of both tumors and individual patients. Here, we discuss how tumor-intrinsic cues, tumor environmental metabolites, and host-derived immune cells might impact the efficacy and resistance often seen during immune checkpoint blockade treatment. Furthermore, we introduce biomarkers identified from human and mouse models that predict clinical benefits for immune checkpoint blockers in cancer.

Fig. 1. Timeline highlights of ICB therapy development within the last three decades.

a Schematic of the mechanism of action of ICB agents. b Timeline highlights of ICB therapy development from its inspection of T-cell activation mechanisms, including the discovery of CTLA-4 and PD-1/PD-L1, to recent clinical trials that are either already approved or are expected to be approved by the FDA

Fig. 2. Prediction of the efficacy of ICBs based on biomarkers identified from biopsies at each time point.

Several longitudinal analyses on genomic and immunologic signatures in biopsies (tissue or blood) of tumor patients pre- or post-ICB treatment suggest novel biomarkers for discriminating responders and non-responders. If patients are predicted to be a non-responder before or after ICB treatment, clinicians can, on an individual basis, determine whether additional therapeutic medications should be applied to resolve resistance associated with poor prognosis

Fig. 3. Tumor-intrinsic and -extrinsic resistance mechanisms to ICBs.

Tumor-intrinsic resistance mainly originates from gain- and loss-of-mutations in oncogenes and tumor suppressor genes, respectively. Mutations resulting in JAK1/2 malfunction break IFN-γ signaling pathways important for chemokine production and MHC I expression. PTEN loss mediates constitutive activation of PI3K to produce VEGF. The expression of MHC I and β2-microbulin (B2M) is also downregulated in patients with no-response to ICBs. Gain-of-function of β-catenin inhibits chemokine expression. In T cells, on the other hand, PD-1-blockade induces alternative TIM-3 (not significantly LAG-3 and CTLA-4) expression to limit activation. ATP metabolites participate in raising the tumor suppressive environment. Tumor suppressive myeloid cells and Treg cells express high levels of CD39 and CD73, degrading ATP and AMP into AMP and adenosine, respectively. Adenosine inhibits effector cell activation while promoting tumor cell proliferation. Adenosine deaminase (ADA) expressed on tumor cells degrades adenosine into inosine. Tumor-associated neutrophils promote tumor metastasis via VEGF/MMPs secretion while anti-tumor effector cells are subverted by IL-10/TGF-β. In addition, tumor-associated fibroblasts also secrete various metastatic/immunosuppressive mediators, which can exacerbate tumor progression