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

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].