Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Abstract

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-β to Overcome Photodynamic Immunotherapy Resistance

“…The downregulation of PD-L1 has been widely recognized as one of the most effective approaches to alleviate T-cell exhaustion. , Therefore, the remaining portion of the tumor tissue from each group was subjected to immunofluorescence analysis to examine the presence of different T lymphocyte populations infiltrating tumors (Figure B). Due to the strong modulation of PD-L1 by anti-PD-L1 and MHI-TMX@ALB, either treatment individually or in combination with PDT, there was a notable enhancement in the infiltration of CD3 + , CD4 + , and CD8 + T-cells into MB49 tumors when treated with MHI-TMX@ALB or anti-PD-L1 monoclonal antibody (Figure B).…”

“…46,52 Thus, the acquired immune resistance after PDT seriously limited its further clinical usage. 18,19 To solve this problem, MHI-TMX@ALB nanoparticles were established in this study (Scheme 1). Unlike some traditional PDT nanosystem encapsulating some typical PDT drugs like verteporfin, IR780, Ce6, SORgenTAM, etc., all-in-one MHI-TMX@ALB nanoparticles had incomparable merits like tumor targeting, self-PD-L1/TGF-β combined depression capacity, and self-hypoxia reversion function, which almost totally reversed acquired immune resistance after PDT.…”

“…Currently, it was widely revealed that extraordinarily tangled and complicated acquired immune resistance is of common occurrence after tumor therapies, including but not only tumor hypoxia, PD-L1 high expression, and enhanced TGF-β secretion. , Taken PDT for example, PDT can enhance immunogenic cell death (ICD) to overcome the intrinsic immune evasion of some low immunogenicity solid tumors as well as enhance cytotoxic T lymphocyte infiltration and its antitumor capacity in tumors. , However, the enhanced secretion of IFN-γ after PDT and induced tumor hypoxia had been identified to partly upregulate PD-L1 through the Janus kinase/signal transducer and activator of the transcription signaling pathway. , Thus, the acquired immune resistance after PDT seriously limited its further clinical usage. , To solve this problem, MHI-TMX@ALB nanoparticles were established in this study (Scheme ). Unlike some traditional PDT nanosystem encapsulating some typical PDT drugs like verteporfin, IR780, Ce6, SORgenTAM, etc., all-in-one MHI-TMX@ALB nanoparticles had incomparable merits like tumor targeting, self-PD-L1/TGF-β combined depression capacity, and self-hypoxia reversion function, which almost totally reversed acquired immune resistance after PDT. ,,, By using such a nanosystem, MHI-TMX@ALB nanoparticles enhanced the CD3 + T-cell, CD4 + T-cell, and CD8 + T-cell infiltration in tumors, which effectively inhibited bladder cancer growth after PDT (Figure ).…”

“…At present, a lot of PDT drugs or PDT drug-loaded nanoparticles like porphyrin analogues, heptamethine cyanine dye, and phenothiazine derivatives were discovered to solve the internal defects of traditional PDT drugs like excessive blood metabolism, low ROS yield ratio, and no tumor-targeting capacity. − Among these superior PDT drugs, heptamethine cyanine dye analogues like IR-780 and MHI-148 derived from clinically approved diagnostic medicine indocyanine green was the most potent, since these molecules selectively accumulate at the tumors and can be excited by near-infrared laser with 8 mm–1 cm depth of tissue penetration. , However, the efficacy of these heptamethine cyanine dyes or these drug-loaded nanoparticles is still seriously restricted due to their disability to regulate the exogenous hypoxia and high PD-L1 and TGF-β expression immune-suppression tumor microenvironment (TME), which then leads to limited ROS generation and possibly further augmented PD-L1 expression mediated by PDT-induced higher IFN-γ expression in vivo . , Currently, to our best knowledge, few PDT drugs except Verteporfin and SORgenTAM are proven to possess the ability to decrease PD-L1 expression or reverse the tumor hypoxia microenvironment. − However, these PDT drugs or nanoparticles still could not solve masses of problems faced by PDT simultaneously. , Therefore, further embellishment of heptamethine cyanine dye to construct a better PDT drug or nanoparticle with self-regulated oxygen, PD-L1, and TGF-β capacity is still urgently needed.…”

Multifunctional Probe Based on “Chemical Antibody–Aptamer” for Noninvasive Detection of PD-L1 Expression in Cancer

“…Tumor cells exploit this molecular mechanism to escape immune surveillance by overexpressing immune checkpoint molecules and promoting tumor growth. In addition, anti-PD-1/PD-L1 immunotherapy characterized by accurate effect, good tolerance, wide indications, and high specificity has shown high efficacy in a wide variety of cancers, such as nonsmall cell lung cancer (NSCLC), colorectal cancer, melanoma, and so on. − However, not all patients respond to the ICI-based treatment, and only 10–30% of patients have just benefited from the therapeutic schedule as a whole. , Researchers indicated that the clinicopathologic features and clinical outcome of patients were closely related to the expression level of PD-L1. − Accordingly, it is essential to accurately select the potential beneficiaries of anti-PD-1/PD-L1 immunotherapy.…”