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Review
. 2020 Jul 21:8:672.
doi: 10.3389/fcell.2020.00672. eCollection 2020.

Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors

Qingyang Lei  1   2   3 , Dan Wang  1   2   3 , Kai Sun  4 , Liping Wang  2 , Yi Zhang  1   2   3   5
Affiliations
Review

Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors

Qingyang Lei et al. Front Cell Dev Biol. .

Abstract

In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-γ signaling, and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

Keywords: PD1; PDL1; cancer; immunotherapy; mechanism; resistance.

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Figures

FIGURE 1
FIGURE 1
Mechanism of PD1/PDL1 blockade. The CD8+ T cell activates upon recognizing the tumor antigen presented on MHC class I and releases IFN-γ to bind to IFN-γ receptor, and consequently induces the expression of PDL1 on tumor cells. PDL1 conjugates the elevated PD1 on T cell surface, triggering inhibitory effect of PD1/PDL1 axis. Anti-PD1 or anti-PDL1 antibody blocks the interaction of PD1 and PDL1, and abolishes the inhibition of CD8+ T cell thus enhancing the antitumor activity.
FIGURE 2
FIGURE 2
Mechanisms of primary resistance. (a) Tumors with high mutation burden are more likely to respond to anti-PD1/PDL1 therapy because there is a greater possibility of generating immunogenic neoantigens which activate CD8+ T cells and induce tumor rejection reactivity. (b) Tumor cells with primary B2M mutation fail to present tumor antigens and elicit antitumor immunity which is required for tumor cell killing. (c) Tumor cells resistant to IFN-γ signaling because of primary JAK1/2 mutation can not induce PDL1 upregulation but inhibit T cell reactivity in PD1/PDL1 independent pathway. The inactivation of IFN-γ signaling also downregulates CXCL9 and CXCL10 expressions which are necessary for T cell trafficking. (d) Alternative immune checkpoints are upregulated in tumor infiltrating T cells, and thus only blocking PD1/PDL1 axis is not enough to rescue the severely exhausted T cells. Upregulation of VEGFR signaling and TOX expression aggravates the activation of inhibitory signaling. (e) TME contains diverse immunosuppressive cells that influence anti-PD1/PDL1 efficacy through inhibiting T cell reactivity. Cytokines derived from tumors recruit more immunosuppressive cells to TME and promote polarization toward pro-tumor phenotype. (f) Oncogene mutation and abnormal activation contribute to inhibition of antitumor immunity, resulting in primary resistance to anti-PD1/PDL1 therapy.
FIGURE 3
FIGURE 3
Mechanisms of acquired resistance. (a) Immunoediting under the pressure applied by PD1/PDL1 blockade selectively preserves tumor cells that have superiority to escape antitumor immunity. (b) Compensatory inhibitory signaling is upregulated in the course of therapy, making it difficult for PD1/PDL1 blockade to reinvigorate CD8+ T cells. (c) If tumor specific T cells fail to become memory T cells, therapy response will not persist and T cells will be re-exhausted.
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