PD-1/PD-L1 Immunotherapy: Combating Drug Resistance in Breast Cancer

Gisha Rose Antony; Sulfath Thottungal Parambil; Ajeesh Babu Littleflower; Lakshmi Subhadradevi

Review Article

Austin J Clin Immunol. 2023; 9(1): 1051.

PD-1/PD-L1 Immunotherapy: Combating Drug Resistance in Breast Cancer

Gisha Rose Antony, Sulfath Thottungal Parambil, Ajeesh Babu Littleflower and Lakshmi Subhadradevi*

Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, India

*Corresponding author: Lakshmi Subhadradevi Additional Professor, Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala-695011, India

Received: January 12, 2023; Accepted: February 14, 2023; Published: February 21, 2023

Abstract

In recent years, immune-checkpoint blocking therapy targeting the PD-1/PD-L1 axis has advanced tumor immunotherapy to a new level, with positive outcomes in a variety of malignant tumors. Tumors can avoid an antigen-specific T cell immune response by means of PD-1/PD-L1 signaling, which adversely controls T cell-mediated immune response. In clinical practice, it was shown that while some patients did have long-term success with immunotherapy, the majority eventually had resistance to drugs and recurrence. Hence, one of the main challenges that severely restricts the long-lasting benefits and widespread use of PD-1/PD-L1 blocking treatment is both primary and acquired resistance. Therefore, it is high time to understand the mechanisms of resistance for improving anti-PD-1/PD-L1 efficacy. In this review, we describe major signaling pathways that regulate PD-1/PD-L1 axis in cancers as well as the role of PD-1/PD-L1 in breast cancer development and progression. In addition, we further discuss the involvement of PD-1/PD-L1 axis in multi-drug resistance in cancers, which affected breast cancer and other solid tumor response rates and durability to treatment strategies.

Keywords: Breast Cancer; Drug Resistance; Immunotherapy; Immune Checkpoints; PD-1/PD-L1

Introduction

Breast Cancer (BC) is the most common female cancer worldwide and the main cause of death, according to the Global Cancer Statistics 2020, surpassing lung cancer [1]. It is a heterogeneous disease that expresses several key proteins as drug targets [2]. Understanding the heterogeneity of the disease has become essential for treatment planning as there are numerous unique subtypes of BC. Triple-Negative Breast Cancer (TNBC) is defined as BC that does not respond to Her2-targeted therapy or hormone therapy and has the worst prognosis of any subtype due to its aggressive nature [3]. Hence, chemotherapy is the treatment option available for the management of TNBC patients.

The immune system plays an integral role in the onset and spread of cancer, and so novel targeted medicines are available. In the tumor microenvironment, the complex interactions of stromal cells, immune effector cells, tumor cells, and various soluble substances play a crucial role in the development and/ or elimination of the disease. Hence, a significant advancement in the treatment of malignant tumors, including BC, is targeting the immune system, immune checkpoint inhibition in particular [4].

Immune-Checkpoints in Cancer

Immune homeostasis maintenance is essential for the proper functioning and survival of the host. Explicit or uncontrolled immune responses against pathogens and mutated or over expressed self-antigens can lead to autoimmune disorders and inflammatory tissue damage. This is prevented by balancing co-stimulatory and inhibitory signals, collectively known as immune checkpoints, to maintain the breadth and amplitude of the immune response [5]. Figure 1 summarizes these co-stimulatory and inhibitory signals. The immune checkpoint receptors, which include Programmed cell Death receptor-1 (PD-1), T cell Immunoglobulin and ITIM domain (TIGIT), Lymphocyte Activation Gene-3 (LAG3), T cell immunoglobulin-3 (TIM3), Cytotoxic T Lymphocyte-Associated molecule-4 (CTLA-4), and B and T cell Lymphocyte Attenuator (BTLA), have been discovered and researched in relation to cancer in past decades [6]. They go by the name “immune checkpoints,” which refers to the molecules that serve as the gatekeepers of the immune system. Since they are surface molecules, antibodies that block the ligand-receptor interaction can easily reduce their function [7]. Targeting these regulatory mechanisms to increase immune response against tumor cells is a promising strategy of immune checkpoint therapy for cancer [8]. Ipilimumab, a monoclonal antibody against CTLA-4 was the first Immune Checkpoint Inhibitor (ICI) approved by the FDA for the management of advanced melanoma in 2011 [9]. However, only a small fraction of patients benefit from the currently approved ICIs, and resistance following an initial response is a frequent occurrence [10]. However, additional stimulatory and inhibitory pathways have shown promise as immune checkpoint treatment targets, and immunotherapy is now going much farther than this strategy. The most effective immune checkpoint blockade therapy till date is the anti-PD-1/PD-L1 axis, which has been approved to treat a variety of cancer types, including those of the bladder, blood, kidney, skin, liver, and lung [11].

Figure 1: The co-inhibitory/stimulatory signals in the immunologic synapse between antigen presenting cell or tumor cell and T cell in the tumor microenvironment.

    
    
    Figure 1: The co-inhibitory/stimulatory signals in the immunologic synapse between antigen presenting cell or tumor cell and T cell in the tumor microenvironment.

The 2018 Nobel Prize in Physiology or Medicine was awarded to the Immune Checkpoint Blockade (ICB) targeting the PD-1/PD-L1 axis, which has been approved for treatment in a variety of solid cancers. Within the tumor microenvironment, the PD-1/PD-L1 pathway regulates the induction and maintenance of immunological tolerance. T cell activation, proliferation, and cytotoxic secretion in cancer are caused by the action of PD-1 and its ligands PD-L1 or PD-L2, which leads to the degeneration of anti-tumor immune responses [12].

Programmed Death Protein-1 (PD-1)

PD-1, also known as CD279, was initially identified in 1992 in interleukin-3 (IL-3)-depleted murine T-cell hybridoma (2B4-11) and murine hematopoietic progenitor (LyD9) cell lines [13]. It is a 55-kDa transmembrane protein with a membrane-permeating domain, an extracellular N-terminal domain (IgV-like), and a cytoplasmic tail with two tyrosine bases situated at the N and C ends, respectively [14]. The amino acid sequence of PD-1 is 15% similar to CD28, 13% similar to the induced T-cell co-stimulator, and 20% similar to CTLA-4 [15]. PD-1 is expressed on the surface of T-cells, B-cells, and NK cells which predominantly controls effector T-cell function in tissues and inhibits their lytic activity in malignancies [16-18]. PD-1 is increased in Dendritic Cells (DCs) by numerous inflammatory stimuli, as it is in T- and B-cells [18]. Although PD-1 is more commonly known as an effectors T cell enhancer in tissues and the tumor microenvironment, it may improve NK cell activity and antibody production by directly and indirectly stimulating PD-1 positive B-cells [19,20]. Due to its potential to be both beneficial and harmful, PD-1 plays two conflicting roles. Owing to its advantageous effects, PD-1 is essential for preserving immunological tolerance and minimizing the regulation of immune responses that are damaging or inefficient. However, PD-1 prevents the proper working of the defense mechanism of the immune system, leading to the growth of malignant cells [21].

Programmed Death Ligand-1 (PD-L1)

PD-L1, a type 1 transmembrane glycoprotein also known as B7-H1 and CD274, is a member of the B7 ligand family. T cells, B cells, macrophages, DC, NK cells, Myeloid-Derived Suppressor Cells (MDSC), and numerous other cell types, including epithelial and endothelial cells, express PD-L1 [22,23]. When tumor cells recognize the PD-1 protein on T cells, PD-L1 protein is up regulated and binds to PD-1 on T cells, causing the T cells to undergo apoptosis and thereby evading the antitumor immunity [24,25]. Therefore, a tumor that over expresses PD-L1 serves to shield itself against CD8+ cytotoxic T cell-mediated cell death. Many studies have reported that the over expression of PD-L1 is associated with an advanced disease state and a poor prognosis in human malignancies such as Non-Small Cell Lung Carcinoma (NSCLC), melanoma, Renal Cell Carcinoma (RCC), gastric, ovarian, and bladder cancer [26-31]. The PD-1/PD-L1 interaction suppresses T-cell activity, decreases cytokine production, causes T-cell lysis, and induces antigen tolerance [32,33]. Indeed, blocking specific immune checkpoints with monoclonal antibodies has been shown to effectively initiate antitumor responses in a variety of solid tumors, including lung, colorectal, ovarian, esophageal, bladder, and BC, in addition to so called "immunogenic" tumor types like melanoma and RCC [34]. Hence, drugs that target PD-1/PD-L1 axis have been developed for immune checkpoint blockade and could trigger responses across various malignancies, providing new hope for the management of cancer. Nevertheless, the clinical response rate to current PD-1/PD-L1 targeted therapies is still low in many patients, and many of them initially respond but eventually develop resistance to these targeted therapies.

PD-1/PD-L1 Pathway in Breast Cancer

By increasing the expression of PD-L1 on the tumor cell surface, the PD-1/PD-L1 inhibitory pathway can be (mis)used to mute the immune system in breast tumors. In our previous study, we have shown that in BC tissues, PD-L1 expression is high more specifically in TNBC subtypes (53.9%) [35]. Increased PD-L1 expression in BC has been associated with increased tumor size, high grade, high proliferation, lymph node status, and HER2-receptor status of the patient [35,36]. According to a recent meta-analysis, BC expressing PD-L1 were more aggressive and had a shorter survival time, whereas TIL expression may be an indicator of a better prognosis [37].

In a study conducted by Schalper et al. (2014) they correlated the PD-L1 mRNA expression with clinicopathological parameters of BC patients. They reported that the PD-L1 mRNA expression on tumor cells is independently associated with increased TIL and better prognosis in BC [38]. Previous study by Mittendorf et al. (2014) also revealed that TNBC has high PD-L1 expression compared to non-TNBC. Furthermore, tissue microarray revealed that breast tumors that were PD-L1 positive had higher TIL in the tumor microenvironment. Their study also revealed that PTEN loss was associated with upregulated PD-L1 expression in BC [39].

PD-1/PD-L1 Inhibitors in Cancer

Since the identification of immune checkpoint proteins, there has been a particular focus on the development of antibodies that inhibit the PD-1/PD-L1 axis. Currently, four mAbs targeting PD-1 and three mAbs targeting PD-L1 have been FDA-approved [40,41] and are undergoing clinical trials for a variety of cancers, which are depicted in Figure 2 and summarized in Table 1, and there are more than fifteen mAbs in clinical development.

Figure 2: The seven mAbs targeting PD-1 (Pembrolizumab, Nivolumab, Cemiplimab, Dostralimab) and PD-L1 (Avelumab, Durvalumab, Atezolizumab) approved for the treatment of various cancers.

    
    
    Figure 2: The seven mAbs targeting PD-1 (Pembrolizumab, Nivolumab, Cemiplimab, Dostralimab) and PD-L1 (Avelumab, Durvalumab, Atezolizumab) approved for the treatment of various cancers.

Table 1: PD-1/PD-L1 inhibitors currently approved by the FDA, along with their indications.




  
    PD-1 Inhibitors
    Company
    Approval Date
    Tumor type
    Mechanism
    Adverse Effects
    References
  
  
    Pembrolizumab

      (MK-3475, Keytruda)
    Merck Sharp & Dohme Corp.
    2014
    
      Melanoma
      NSCLC
      HNSCC
      MSI-H or dMMR solid tumors
    
    Block the PD-1 receptor pathway by binding to the PD-1 receptor.
    
      Fatigue
      Musculoskeletal pain
      Decreased appetite
      Pruritus
      Diarrhea
      Nausea
      Rash
      Pyrexia
      Cough
      Dyspnea
      Constipation
      Abdominal pain
      Pneumonia
      Nephritis
      Hepatitis
      Myocarditis
      Colitis
    
       
    [43-45]
  
  
    Nivolumab

      (OPDIVO, ONO4538, MDX-1106

      BMS-936,558)
    Bristol-Myers Squibb
    2014
    
      Melanoma
      NSCLC
      SCLC
      RCC
      UC
      HNSCC
    
    Selectively block the PD-1 receptor interaction with PD-L1/PD-L2    by binding to PD-1 receptor.
    
      Increased risk of severe immune    mediated inflammation in the lungs, colon, liver and the kidneys.
      Immune-mediated hypothyroidism and    hyperthyroidism
      Auto immune diabetes
    
    [46-49]
  
  
    Cemiplimab

      (REGN2810, SAR439684, Libtayo)
    Sanofi/Regeneron
    2018
    
      CSCC
    
    Binding to the PD-1 receptor and blocks the interaction with    PD-L1.
    
      Immune-mediated pneumonia
      Colitis
      Hepatitis
      Endocrine disorders
      Skin adverse reactions
      Nephritis
      Renal dysfunction
      Fatigue
      Rash
      Diarrhea
    
    [50-52]
  
  
    Dostarlimab

      (Jemperli, TSR-042)
    GlaxoSmithKline LLC
    2021
    
      MSI-H or dMMRsolid tumors
    
    Binding to the PD-1 receptor and prevents the interaction with    PD-L1and PD-L2.
    
      Fatigue
      Musculoskeletal pain
      Diarrhea
      Nausea
      Rash
      Pyrexia
      Constipation
      hypothyroidism
    
    [41,53-55]
  
  
    PD-L1 Inhibitors
    Company
    Approval Date
    Tumor type
    Mechanism
    Adverse Effects
    References
  
  
    Atezolizumab

      (MPDL3280A, Tecentriq)
    Roche Genentech
    2016
    
      NSCLC
      UC
      ES-SCLC
      TNBC
    
    Prevents the interaction of PD-L1 specifically on tumor cells    with PD-1 and CD80 receptors and enhances the T-cell mediated antitumor    immunity.
    
      Fatigue/weakness
      Nausea
      Cough
      Dyspnea
      Decreased appetite
      Urinary tract infection
    
    [56-59]
  
  
    Avelumab

      (MSB0010718C, Bavencio)
    Merck KGaA and Pfizer
    2017
    
      MCC
      RCC
      UC
    
    Inhibits the PD-1/PD-L1 interactions while maintaining the    PD-1/PD-L2 pathway.
    
      Pneumonia
      Hepatitis
      Colitis
      Adrenal insufficiency
      Hyperthyroidism
      Diabetes
      Nephritis
      Fatigue
      Musculoskeletal pain
      Diarrhea
      Nausea
      Infusion-related reactions
      Rash
      Decreased appetite
      Peripheral edema
      Urinary tract infections
    
    [60-60]
  
  
    Durvalumab

      (MEDI4736, Imfinzi)
    Medimmune/

      AstraZenecak
    2017
    
      UC
      NSCLC
    
    Block the binding of PD-L1 with PD-1 and CD80 receptors.
    
      Fatigue
      Musculoskeletal pain
      Constipation
      Decreased appetite
      Nausea
      Peripheral edema
      Urinary tract infections
      Cough
      Dyspnea
      Rash
      Dehydration
    
    [63-65]
  
  
    NSCLC: Non-Small Cell Lung Cancer; HNSCC:    Head & Neck Squamous Cell Carcinoma; SCLC: Small Cell Lung Cancer; RCC:    Renal Cell Carcinoma; UC: Urothelial Cancer; CSCC: Cutaneous Squamous Cell    Carcinoma; ES-SCLC: Extensive-Stage Small Cell Lung Cancer; MCC: Merkel Cell    Carcinoma; MSI-H/dMMR tumors: Microsatellite Instability-High/Mismatch Repair    Deficient Tumors.



Table 1: PD-1/PD-L1 inhibitors currently approved by the FDA, along with their indications.

Tumors can avoid anti-PD-1/PD-L1 therapy by creating a hostile Tumor Microenvironment (TME) that reduces the antitumor effectiveness of T cells. Irreversible T cell exhaustion, dysfunction of antigen presentation, inadequate antigen immunogenicity, immunosuppressive TME, and resistance to IFN-^γ signaling may all contribute to this [42].

Regulation of PD-1/PD-L1 Pathway in Cancer

Various signaling pathways (Figure 3) are known to be involved in the modulation of the PD-1/PD-L1 axis in cancer and exert a major role in tumorigenesis. Therefore, it is necessary to understand these signaling networks more deeply in order to improve our current knowledge.

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Citation: Antony GR, Parambil ST, Littleflower AB, Subhadradevi L. PD-1/PD-L1 Immunotherapy: Combating Drug Resistance in Breast Cancer. Austin J Clin Immunol. 2023; 9(1): 1051.

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