Clinical implication of serologic indexes and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy

Abstract

Background Immune checkpoint blockers (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor outcomes. This study aimed to determine differences in factors among patients with non-small cell lung cancer (NSCLC) displaying different tumor responses to immunotherapy. Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤ 2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Twenty-six patients (11.3%) met the HPD criteria. HPD was more frequent in patients with oncogenic driver mutations, ≥ 3 metastatic sites, ≥ 4 prior systemic treatments, and low PD-L1 expression (< 10%). Serological indexes at the first response evaluation were significantly associated with HPD. The number of CD4 + effector T cells and CD8 + cytotoxic T cells, and CD8+/PD-1 + tumor-infiltrating lymphocytes tended to be smaller, especially in stromata of HPD group. While in the stromal region, there were more M2-type macrophages expressing CD14, CD68 and CD163, and remarkably fewer intratumoral CD56 + NK cells in HPD. Conclusions These results indicate that oncogenic driver mutations, multiple metastatic sites, serological markers, fewer CD8+/PD-1 + cells, and more M2 macrophages in the tumor microenvironment predict HPD in advanced/metastatic NSCLC patients undergoing immunotherapy.