The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis

BackgroundThe responses of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing tumor cells. This study aims to evaluate the prognostic role of CD8+ TILs in cancer patients treated with ICIs.MethodsWe systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 12 Jul 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting efficacy and survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The study protocol is prospectively registered on PROSPERO (registration number CRD42021233654).FindingsFindings: A total of 33 studies consisting of 2559 cancer patients were included. The result showed that high CD8+ TILs were significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41–0.67; p < 0.001), PFS (HR, 0.52; 95% confidence interval: 0.40–0.67; p < 0.001) and ORR (OR, 4.08; 95% confidence interval: 2.73–6.10; p < 0.001) in patients treated with ICIs. Subgroup analyses suggested that patients with high CD8+ TILs had a better clinical benefit, regardless of different treatments (ICI mono therapy, or combination therapy), cancer types (NSCLC, melanoma and others), and CD8+ T cells locations (intra-tumor, stroma, and invasive margin). The higher baseline circulating CD8+ T cells from peripheral blood did not contribute to the improved OS (HR, 0.93; 95% confidence interval: 0.67–1.29; p = 0.67) and PFS (HR, 0.89; 95% confidence interval: 0.60–1.32; p = 0.56) compared with the low baseline.InterpretationInterpretation: Our results suggested that high intra-tumoral, stromal, or invasive marginal, but not circulating CD8+ T cells, can predict treatment outcomes in patients with ICIs therapy across different cancers, in either single-agent ICIs or combination with other therapies.FundingFunding: China National Science Foundation (Grant No. 82,022,048, 81,871,893), Key Project of Guangzhou Scientific Research Project (Grant No. 201,804,020,030), High-level university construction project of Guangzhou medical university (Grant No. 20,182,737, 201,721,007, 201,715,907, 2,017,160,107); National key R & D Program (Grant No. 2017YFC0907903 & 2017YFC0112704) and the Guangdong high level hospital construction "reaching peak" plan.