The cutting-edge progress of immune-checkpoint blockade in lung cancer

Abstract

Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer. Immune-checkpoint inhibitor (ICI) treatment, either as monotherapy or combination therapy, has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer. An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy. Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection, both of these biomarkers are imperfect. Due to the complex cancer-immune interactions among tumor cells, the tumor microenvironment and host immunity, collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy. Furthermore, as a result of the wide use of ICIs, managing acquired resistance to ICI treatment remains an inevitable challenge. A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles. In this review, we describe the cutting-edge progress made in patients with lung cancer, the optimal duration of ICI treatment, ICIs in some special populations, the unique response patterns during ICI treatment, the emerging predictive biomarkers, and our understanding of primary and acquired resistance mechanisms to ICI treatment.

Keywords: acquired resistance; immune-checkpoint inhibitor; lung cancer; predictive biomarker.

Fig. 1

Timeline of the major progress made in immune checkpoint inhibitors in the management of lung cancer. NMPA, National Medical Products Administration; FDA, Food and Drug Administration; 2L, second-line; SQ, squamous cell carcinoma; NSCLC, non-small cell lung cancer; 1L, first-line; NSQ, non-squamous cell carcinoma; ES-SCLC, extensive stage small cell lung cancer; TC, tumor cell; IC, immune cell; ABCP, Atezolizumab + Bevacizumab + Carboplatin + Paclitaxel

Fig. 2

Potential biomarkers for the response to immune checkpoint inhibitors. APC, antigen presenting cell; NK cell, natural killer cell; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; Treg, regulatory T cell; CAF, cancer-associated fibroblast; TMB, tumor mutational burden; GEP, gene expression profiling; TCR, T cell receptor; TME, tumor microenvironment; bTMB, blood tumor mutational burden; ctDNA, circulating tumor DNA; TILs, tumor-infiltrating lymphocytes; dMMR, mismatch repair-deficient; MSI, microsatellite instability; DDR, DNA damage repair