Deep learning-based immune phenotype analysis reveals distinct resistance pattern of immune checkpoint inhibitor in non-small cell lung cancer.

Abstract

3119 Background: Resistance pattern and biological mechanism of immune checkpoint inhibitor (ICI) has been poorly understood. Sine suggested resistance mechanisms would be either innate resistance caused by lack of immune recruitment or acquired immune evasion after durable response of ICI treatment, we hypothesized that resistance pattern of tumor microenvironment would be distinct according to duration of ICI response in non-small cell lung carcinoma (NSCLC). In the current study, we applied deep-learning-based classification of three immune phenotypes (3IP): inflamed, excluded, and desert, to objectively assess the immunologic status of tumor microenvironment. Methods: Deep-learning algorithm of H&E Whole-Slide Images (WSI), called Lunit-SCOPE, was trained with 1,824 H&E WSI of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches and each patch (~10 high-power fields) was classified as inflamed, excluded and desert, based on both quantity and localization of immune cells. Among NSCLC patients treated with ICI in SMC, 87 paired treatment-naïve (Pre, patch N = 15,415) and post-progression (Post, patch N = 18,197) tumor tissues were analyzed for Lunit-SCOPE. Results: In 87-paired samples, proportions of excluded and desert phenotypes were increased in post-progression tumor tissues (excluded; Pre 26.8% versus Post 32.5%, desert; Pre 19.5% versus Post 25.3%). Focused on 29 patients classified as inflamed in treatment-naïve, proportion of immune phenotypes of post-progression were clearly different according to duration of response, divided by median progression-free survival (PFS) of 3.7 m. Patients with rapid progression without ICI response (PFS < 3.7 m) turned into desert type (46.2%), whereas durable responder (PFS ≥ 3.7 m) either still remained on inflamed phenotype (42.9%) or turned into excluded phenotype (21.4%). Patients who remained on inflamed phenotype had favorable overall survival after progression on ICI, compared to turned into desert type (median survival not reached versus 6.6 m, P= 0.0296). Conclusions: Resistance patterns of ICI are distinct according to duration of response in patients with inflamed phenotype. Rapid progressor turns off immune into desert phenotype whereas most durable responder keeps immune recruitment into tumor microenvironment, which needs tailored strategy to overcome ICI resistance.