Table 2.

Summary of cytokines and soluble factors associated with immunotherapy response.

Marker	Cancer Type	Treatment	N	Findings Associated with Clinical Response	Reference
IL-6	NSCLC	PD-(L)1 inhibitors	47	On-treatment decrease in IL-6 level was associated with improved PFS.	Keegan et al., 2020 [70]
IL-8	Melanoma, NSCLC	PD-1 inhibitors ± Ipilimumab	44 /19	On-treatment decrease in serum IL-8 level could be used to monitor and predict clinical benefit from ICIs (AUC 0.97 among three different patient groups).	Sanmamed et al., 2017 [72]
	UC, RCC	Atezolizumab	1445	High baseline levels of IL-8 were associated with decreased efficacy of atezolizumab. On-treatment decrease in IL-8 was correlated with improved OS.	Yuen et al., 2020 [71]
IL-10	Melanoma	Ipilimumab	35	Combination of IL-10 and TGF-β was associated with PFS.	Tarhini et al. 2015 [73]
	Melanoma	PD-1 inhibitors	18	Higher baseline IFN-γ/IL-10 ratio in PBMCs predicted longer PFS (AUC 0.96).	Giunta et al., 2020 [74]
Soluble CTLA-4	Melanoma	Ipilimumab	113	Higher serum levels of soluble CTLA-4 at baseline were associated with better ORR and OS.	Pistillo et al., 2018 [75]
Soluble PD-1/ PD-L1	Melanoma	PD-1 inhibitors	222	Elevated baseline serum PD-1 or PD-L1 levels predicted poor outcome (AUC 0.61 for sPD-L1 and 0.53 for sPD-1 in OS).	Ugurel et al., 2020 [76]
CRP	Various solid tumors	PD-1 inhibitors	326	Elevated baseline CRP was an indicator of poor RFS and OS.	Livanainen et al., 2019 [77]
	RCC	Nivolumab	42	The early on-treatment CRP flare-response was associated with tumor shrinkage and improved survival outcomes.	Fukuda et al., 2021 [78]
LDH	Various solid tumors	Immunotherapy	155	High baseline LDH levels were correlated with poor OS.	Bigot et al., 2017 [79]
	Melanoma	Pembrolizumab	616	Low pretreatment values of LDH were associated with favorable OS.	Weide et al., 2016 [80]
CTCs	NSCLC	PD-(L)1 inhibitors	104	The presence of CTC is a predictive factor for a worse durable response rate to ICI.	Tamminga et al., 2019 [81]
ctDNA	NSCLC	Durvalumab	28	A drop in the ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with ICIs.	Raja et al., 2018 [82]
	NSCLC	Pembrolizumab + chemotherapy	62	Decreases in ctDNA levels were related with clinical benefit.	Ricciuti et al., 2021 [83]
	Various solid tumors	Pembrolizumab	94	Baseline ctDNA levels were correlated with PFS, OS, and clinical response.	Bratman et al., 2020 [84]
bTMB	NSCLC	PD-(L)1 inhibitors	98	ctDNA-based bTMB could be used as a potential biomarker for anti-PD-1 and anti-PD-L1 treatment in patients with NSCLC.	Wang et al., 2019 [60]
	NSCLC	Atezolizumab	216	High bTMB is a clinically actionable biomarker for atezolizumab.	Gandara et al., 2018 [85]
Exosome	Melanoma	Pembrolizumab	44	Lower baseline levels of exosomal PD-L1 and their increase during treatment were correlated with tumor response (AUC 0.91 for exosomal PD-L1, 0.70 for total PD-L1).	Chen et al., 2018 [86]
	Melanoma	Ipilimumab	59	Increased exosomal PD-1, and the CD28 levels in T cells were associated with longer PFS and OS.	Tucci et al., 2018 [87]