Causal effects of immune cells on the efficacy and adverse drug reactions of platinum drugs

Abstract

Platinum drugs are widely used in lung cancer chemotherapy, but the immune characteristics of different individuals have different effects on the sensitivity and side effects of platinum drugs. In this study, we use 731 kinds of immune cell traits of 3757 healthy individuals and 429 patients with non-small cell lung cancer (NSCLC) in Xiangya Hospital of Central South University to conduct a Mendel randomized analysis in order to find out the causal relationship between some immune cell traits and the efficacy and adverse reactions of platinum drugs. We find that CD19 on CD24+CD27+ B cell (OR = 0.598, P = 0.004) is the most significant immune cell trait as the protective factor of efficacy. HLA-DR+CD8+ T cell % lymphocyte (OR = 0.427, P = 7.55 × 10–4) and HLA-DR+CD8+ T cell % T cell (OR = 0.471, P = 0.003) are the protective factors of liver injury. CD39 on CD39+ secreting CD4+ regulatory T cell (OR = 28.729, P = 0.009) and CD3 on CD39+ resting CD4 regulatory T cell (OR = 3.024, P = 0.009) are the risk factors of renal injury. Meanwhile, B cell-related traits mainly affect gastrointestinal upset and cutaneous toxicity, while T cell-related traits mainly affect other outcome variables. These findings may promote our understanding of the relationship between the efficacy and adverse reactions of platinum drugs and the immune system, and promote future development of biomarkers for predicting the efficacy and adverse reactions of platinum drugs.

1. Introduction

Cancer remains the leading cause of human death despite the innovation of medical technology and the significantly improved life span of human beings [1]. The incidence of cancer has been increasing annually because of environmental, diet, and stress factors, and it is all in the late stage when it is discovered [2]. Nowadays, cancer treatment strategies, from radiotherapy and chemotherapy, surgery to immunotherapy, targeted therapy, and then cell therapy have greatly improved cancer treatment and prognosis [3]. However, radiotherapy and chemotherapy remain the basic schemes of tumor treatment, among which platinum drugs have been administered in tumor treatment since the 1970s and are still widely used in various tumors [4], such as oral squamous cell carcinoma, lung cancer, ovarian cancer, colorectal cancer, and breast cancer [5]. Platinum drugs are the basic drugs for treating malignant tumors at present, which exhibit a wide antitumor spectrum, inhibit DNA transcription and replication, promote tumor cell apoptosis, and play a therapeutic role [6]. The efficacy and adverse drug reactions of drugs are crucial indicators to assess the clinical value of drugs. Platinum drugs play an important role in treating malignant tumors, but they destroy normal body tissues while acting on tumor cells, thereby causing adverse drug reactions of different degrees [7]. Adverse drug reactions not only reduce the quality of life of patients but also delay or interrupt the treatment course and affect the treatment efficacy when they are serious.

Cis-dichloroplatinum demonstrated remarkable activity in treating advanced testicular cancer in the late 1970s [8]. It was then tested in various tumor types and is now the approved first-line therapeutic agent for advanced non-small cell lung cancer and ovarian cancer, head and neck cancer, cervical cancer, and bladder cancer, among which platinum is the most predominantly used chemotherapy drug category [9]. Cisplatin and carboplatin exhibited moderate activity as single drugs in patients with advanced non-small cell lung cancer [10], but the survival rate can be improved when combined with other chemotherapy drugs. However, it demonstrates many adverse drug reactions, such as inhibiting cellular and humoral immunity [11]. Studies have revealed that CD4+ T cells and CD8+ T cells [text truncated]