Among 2928 articles identified from the literature search in MEDLINE, Embase, the Cochrane Library, and Web of Science, 301 full-text articles were assessed for eligibility. A total of 265 studies were excluded because of not specified population (n=73) or treatment (n=24), without biomarkers (n=44) or outcome indicators (n=71), small sample size (n=9), or article type (n=41). Additionally, 3 studies were excluded because their original data could not be accurately extracted and the authors could not be reached [23,24,25]. At last, 36 studies were eligible for the systematic review, and 35 of them with 1829 patients were included in the meta-analysis (Fig. 1).
Fig. 1Flow diagram of study selection, compliant with the PRISMA
Study characteristics of included studiesThe general characteristics are shown in Table 1. All included studies were published from 2015. Sample sizes varied from 10 to 119, with 21 being multi-centered clinical trials. Two studies recruited participants globally [4, 26], and the rest were conducted in East Asia (n=15), North America (n=14), and Europe (n=5).
Table 1 General characteristics of the included studiesMost included studies focused on metastatic CRC patients, except one focused on rectal cancer in locally advanced stage [27]. Tumors with pMMR/MSS characteristic comprised the majority in most studies (n=20), whereas dMMR/MSI-H tumors were required in 12 studies. For treatment strategies, there were 8 studies focused on ICI monotherapy [3, 4, 26, 28,29,30,31,32], all of which were anti-PD1 therapy, and 9 studies permitted or applied dual ICI therapy [33,34,35,36,37,38,39,40,41]. Moreover, the majority of the studies applied combined therapies with ICIs, involving vascular endothelial growth factor receptor inhibitors (VEGFRi, n=9) [42,43,44,45,46,47,48,49,50], chemoradiotherapy (n=5) [10, 15, 27, 50, 51], other investigational agents (n=5) [52,53,54,55,56] and Cetuximab, an epidermal growth factor receptor blockade (n=1) [57]. Detailed information can be achieved from Supplementary Table 2.
Most of the included studies were at low risk of bias (30 out of 36, Table 1), while the rest owned a moderate risk, mainly attributed to their retrospective study design and lack of control for confounding factors. The NOS scores are presented in Supplementary Table 3 in detail.
Low pretreatment blood neutrophil-to-lymphocyte ratio (NLR) predicts good prognosis for CRC patients upon ICIsNLR is the absolute neutrophil count divided by the absolute lymphocyte count obtained from the blood count [54, 57]. Pre-treatment NLR was assessed in 6 studies [29, 33, 34, 44, 54, 57], with cutoffs ranging from 1.5 to 5.
For CRC patients treated with ICIs, those with a low pretreatment NLR show less risk of death than those with a high pretreatment NLR (n=4 studies, HR 0.37, 95%CI 0.21–0.67, I2=59%, p=0.06)(Fig. 2A) [29, 33, 54, 57], with robustness verified (Supplementary Fig. 1A). The subgroup analysis (Table 2) showed that the moderate heterogenicity could be attributed to different treatment strategies. Besides, using 5 as the cutoff value may be more efficient than a value less than 5.
Fig. 2Forest plots for pretreatment blood neutrophil-to-lymphocyte ratio (NLR) on overall survival (A), progression-free survival (B), and objective response rate (C) in CRC patients treated with ICIs
Table 2 Results of the subgroup analysisFurthermore, low pretreatment NLR predicted a slow disease progression of CRC during the treatment of ICIs (n=5 studies, HR 0.60, 95%CI 0.45– 0.80, I2=0%, p=0.46) (Fig. 2B) [33, 34, 44, 54, 57]. According to sensitivity analysis, NLR derived from the difference between leukocytes and neutrophils could be used as a substitute (HR 0.59, 95%CI 0.42–0.83)(Supplementary Figure 1B) [34].
However, the pooled OR for response to treatment was 1.73 (n=3 studies, 95% CI 0.65–4.61, low versus high NLR, I2=0%, p=0.67)(Fig. 2C) [33, 54, 57], suggesting that a pre-treatment low NLR showed a trend but was insufficient to predict shrinkage of tumor upon ICI treatment.
Tumor PD-L1 expression in predicting response of CRC patients upon anti-PD-1/PD-L1 therapyWe included 9 studies using high or positive expression of tumor PD-L1 as a biomarker for ICIs [3, 4, 26, 31, 41, 42, 51, 52, 55]. However, PD-L1 expression was insufficient to predict tumor response to ICI treatment (OR 1.01, 95%CI 0.48–2.14, high versus low expression, I2=19%, p=0.26)(Fig. 3A, Supplementary Figure 1C). Of note, two criteria were reported to evaluate the level of PD-L1 expression in studies. The combined positive score (CPS) was used in 5 studies (OR 0.98, 95%CI 0.34–2.81) [31, 41, 42, 52, 55], calculated by the count of PD-L1 positive tumor cells and immune cells divided by the total number of tumor cells multiplied by 100. Tumor tissue with CPS>1 was considered high or positive in PD-L1 expression. Additionally, 3 articles (OR 0.85, 95%CI 0.27–2.67) used a 5% cutoff value to count the PD-L1 on tumor cells, separating from immune cells [3, 4, 51]. Neither of these evaluation criteria could rescue the inadequate predictive value of tumor PD-L1 expression for ICI treatment in CRC patients (Table 2).
Fig. 3Forest plots for PD-L1 expression on objective response rate (A) and progression-free survival (B). Forest plots for tumor mutation burden (TMB) on objective response rate (C). Funnel plot for publication bias regarding TMB in CRC patients treated with ICIs (D)
In terms of disease progression, a high expression of PD-L1 in tumor tissue seems to be a mild but not significant risk factor for CRC patients under the situation of anti-PD therapy (n=3 studies, HR 1.13, 95%CI 0.55–2.32, I2=41%, p=0.18) (Fig. 2B, Supplementary Figure 1D) [3, 47, 51].
Tumor mutation burden (TMB) predicts efficacy of immunotherapy in CRC patientsWe enrolled 12 studies relevant to TMB. TMB is generally defined as the number of somatic non-synonymous mutations in the tumor tissue derived from the NGS as recommended, sometimes with synonymous mutations [28, 39]. A few cases also used the whole exome sequencing technique to detect TMB [10, 53].
CRC patients with a TMB-high tumor are more likely to respond to ICI treatment compared with a TMB-low tumor (n=10 studies, OR 4.83, 95%CI 2.16–10.78, I2=24%, p=0.23) (Fig. 3C, Supplementary Figure 1E) [3, 10, 28,
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