Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs.

Keywords: PD-1/PD-L1; combination therapy; immune checkpoint inhibitor; resistance; triple-negative breast cancer.

Figure 1

PD-1/PD-L1-mediated inhibition of T cell activation. The binding of PD-1 to PD-L1 recruits SHP-2, thereby weakening the TCR signaling pathway mediated by LCK and inhibiting the RAS-MEK-ERK and PI3K-Akt-mTOR pathways. In addition, PD-1 activation induces the expression of BTAF, which inhibits the expression of effectors for T cell activation. Collectively, the activation of T cells can be inhibited by PD-1/PD-L1-mediated inhibiting of these signaling pathways. Abbreviations: PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell; ITIM, immunoreceptor tyrosine inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; P, phosphorylation; LCK, lymphocyte-specific protein-tyrosine kinase; ZAP70, zeta chain of T cell receptor associated protein kinase 70; SHP-2, src homology-2 domain-containing protein tyrosine phosphatase; BATF, basic leucine zipper transcriptional factor ATF-like; RAS, rat sarcoma; MEK, mitogen-activated extracellular signal-regulated kinase; ERK, extracellular regulated protein kinase; NFAT, nuclear factor of activated T cell; CK2, casein kinase II; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-B.

Figure 2

Immunosuppressive tumor microenvironment in anti-PD-1/PD-L1 therapy. TNBC cells can directly inhibit the activity of effector T cells by upregulating PD-L1 and releasing TGF-β2 and IL-10. Additionally, immunosuppressive cells, including TAM, Tregs and MDSCs, are recruited to the tumor microenvironment, where they can inhibit the anti-tumor of T cells. TAM can also promote tumor cell proliferation by secreting EGF and PDGF, facilitates tumor invasion and metastasis by releasing pro-tumor cell metastasis factors such as MMPs, triggers immune escape of tumor cells by producing IL-10, PGE2, TGF-β and CSF-1, as well as contributes to tumor microvascular growth by expressing VEGF. Abbreviations: PD-1, Programmed cell death-1; PD-L1, Programmed cell death-ligand-1; CSF1, colony stimulating factor 1; CCL2, C-C motif ligand 2; CCL22, C-C motif ligand 22; TGF-β, transforming growth factor-β; IL-6, interleukin-6; IL-10, interleukin-10; IL-35, interleukin-35; NOS, nitric oxide synthase; EGF, endothelial growth factor; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor; MMPs, matrix metallopeptidase; PGE2, Prostaglandin E2; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage.

Figure 3

Disturbed IFN-γ signaling pathway results in resistance to anti-PD-1/PD-L1 therapy. IFN-γ secreted by T cells binds to IFNγR1/2 on the surface of TNBC cells, activating the JAK1/1-STAT1/2 pathway. The phosphorylated STAT1/2 translocates to the nucleus where it binds to GAS and ISRE, promoting the expression of MHC-II, PD-L1 and CXCL9/10. After receiving immunotherapy, tumor cells may downregulate or alter the IFN-γ signaling pathway, such as by reducing JAK1/2 activity to escape the anti-tumor effects of T cell-derived IFN-γ. Abbreviations: PD-L1, programmed cell death 1 ligand 1; TCR, T cell receptor; MHC-Ⅰ, major histocompatibility complex class Ⅰ; IFN-γ, interferon-γ; IFNγR 1/2, interferon-γ receptor 1/2; JAK 1/2, Janus kinase 1/2; STAT 1/2, signal transducer and activator of transcription 1/2; GAS, growth arrest-specific protein; ISRE, interferon-sensitive response element; CXCL9/10, C-X-C motif chemokine 9/10; TNBC, triple negative breast cancer.

Figure 4

T cell exhaustion contributes to therapeutic resistance of TNBC to PD-1/PD-L1 inhibitors. Continuous exposure of T cells to tumor antigens and suppressive cytokines (IL-10, TGF-β) leads to T cell exhaustion, which results in a poor response to immunotherapy and therapeutic resistance. The accumulated ROS, increased HIF-α and activated calcium-calcineurin-NFAT signaling pathway play a key role in T cell exhaustion, which contributes to therapeutic resistance. Abbreviations: PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell; TNBC, triple negative breast cancer; TIM-3, T cell immunoglobulin domain and mucin domain-3; TGF-β, transforming growth factor-beta; IL-10, interleukin-10; IL-1, interleukin-1; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species; NFAT, nuclear factor of activated T cells; HIF-1α, hypoxia inducible factor-1α; TOX, thymocyte selection associated high mobility group box; BATF, basic leucine zipper transcriptional factor ATF-like; IFR-4, interferon regulatory factor 4.

Figure 5

Inhibitory immune checkpoints for TNBC. TNBC cells express immune checkpoint ligands, which mediate resistance to PD-1/PD-L1 inhibitors by inhibiting T cell function. After the PD-1/PD-L1 signaling pathway is blocked by inhibitors, other immune checkpoints, such as CTLA-4, TIGIT, TIM-3 and LAG-3, are compensated upregulated. Abbreviations: PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TIGIT, T cell immunoglobulin and ITIM domain; TIM-3, T cell immunoglobulin domain and mucin domain-3; LAG-3, lymphocyte activation gene-3; TCR, T cell receptor; MHC-II, major histocompatibility complex class II; TNBC, triple negative breast cancer.

Figure 6

Combination therapies with anti-PD-1/PD-L1 antibodies. Combination therapies: including PD-1/PD-L1 antibodies along with radiotherapy, chemotherapy, other immune checkpoint antibodies, targeted therapy, oncolytic viruses and neoantigen-based immunotherapy are being developed to treat cancer patients effectively. Abbreviations: PD-1, Programmed cell death-1; PD-L1, Programmed cell death-ligand-1; CTLA-4, Cytotoxic T Lymphocyte-Associated Antigen-4; TIGIT, T cell immunoglobulin and ITIM domains; ITIM, immunoreceptor tyrosine-based inhibitory motif; TIM-3, T cell immunoglobulin domain and mucin domain-3; IDO, indoleamine 2, 3 dioxygenase; Siglec-15, Sialic Acid Binding Ig Like Lectin-15; PPAP inhibitors, Poly ADP-ribosepolymerase inhibitor; EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; VEGF antibody, vascular endothelial growth factor antibody; CKD4/6 inhibitors, cyclin dependent kinase4/6 inhibitors.