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

Feng Li; Caichen Li; Xiuyu Cai; Zhanhong Xie; Liquan Zhou; Bo Cheng; Ran Zhong; Shan Xiong; Jianfu Li; Zhuxing Chen; Ziwen Yu; Jianxing He; Wenhua Liang

doi:10.1016/j.eclinm.2021.101134

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

EClinicalMedicine. 2021 Sep 16:41:101134. doi: 10.1016/j.eclinm.2021.101134. eCollection 2021 Nov.

Authors

Feng Li¹, Caichen Li¹, Xiuyu Cai², Zhanhong Xie³, Liquan Zhou^{1

4}, Bo Cheng¹, Ran Zhong¹, Shan Xiong¹, Jianfu Li¹, Zhuxing Chen¹, Ziwen Yu¹, Jianxing He¹, Wenhua Liang¹

Affiliations

¹ Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, China.
² Department of General Internal Medicine, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
³ Department of Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, Guangzhou, China.
⁴ The First Clinical College, Guangzhou Medical University, Guangzhou, China.

Abstract

Background: The 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.

Methods: We 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).

Findings: Findings: 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.

Interpretation: Interpretation: 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.

Funding: Funding: 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.

Keywords: Biomarker; CD8+ tumor infiltrating lymphocytes; Cancer; Immune checkpoint inhibitors; Survival.