Biomarkers for response to immune checkpoint inhibitors in gastrointestinal cancers

Table 1 Summary of biomarkers used or worthwhile in gastrointestinal cancers

Classification	Biomarkers	Tumors	Response	OS	PFS	Others	Ref.
Tumor-genome biomarkers	TMB	Multiple GI	Pos/Neg1	14.6/4.0 mo	Unreached/2 mo (CRC)	NA	[19-21]
	dMMR/MSI-H	Multiple GI	Pos	Unreached vs 5.0 mo (CRC)	Unreached vs 2.2 mo (CRC)	Higher DCB (59.1% vs 28.6%, GI tumors)	[30,31]
	CNA	Multiple GI	Neg	Unreached2	Over 10 mo	NA	[31]
	IFN-γ-related	Multiple GI	Pos	Positive correlation (GC)	Positive correlation (GC and ESCA)	NA	[40,42]
	MDM2	HCC	Neg	NA	NA	Correlated with HPD	[50]
TME biomarkers	PD-L1	Multiple GI	Pos	NA	NA	NA	[53,54]
	TIL	Multiple GI	Pos	Prolonged OS (ESCA)	NA	3-yr RFS 71.6% vs 55.3% (CRC)	[67,78]
Liquid-biopsy biomarkers	ctDNA	Multiple GI	Neg	NA	4.9 mo vs 7.4 mo (GC)	2-yr RFS 66% vs 100% (CRC)	[73,74]
	Exosome	GC	Neg	Reduced OS	NA	High level Exosome	[78]

¹In tumor mutation burden (TMB), the Neg means that immune checkpoint inhibitor treatment response of TMB-L patients may be better by epigenetic modifications.

²Represent a wide variety of gastrointestinal tumors and do not refer to any particular type.

OS: Overall survival; PFS: Progression-free survival; TMB: Tumor mutation burden; dMMR: Mismatch repair deficiency; MSI-H: Highly microsatellite instability; CNA: Copy number alteration; TIL: Tumor infiltrating lymphocyte; ctDNA: Circulating tumor DNA; GI: Gastrointestinal; GC: Gastric cancer; CRC: Colorectal cancer; HCC: Hepatocellular cancer; ESCA: Esophageal cancer; HPD: Hyperprogressive disease; DCB: Durable clinical benefit; RFS: Recurrence free survival; Pos: Positive; Neg: Negative; NA: Not applicable; ICI: Immune checkpoint inhibitor.

Table 2 Summary of biomarkers worthy of further development in gastrointestinal tumors

Classification	Biomarkers	Tumor type	Response to ICI	Ref.
Tumor-genome biomarkers	POLE-mutation	Endometrial carcinoma	Pos	[93]
	Neoantigen	Pulmonary adenocarcinoma	Pos	[94]
Liquid-biopsy biomarkers	LDH	Melanoma	Neg	[99]
	NLR	Advanced solid tumors	Neg	[100]
Epigenetic	TET1-mutation	Multiple tumor types	Pos	[105]
	miRNA	Non-small-cell lung cancer	Pos	[107]
Patient characteristic	Gender	NA	Male: Pos; Female: Neg	[81,82]
	Age	NA	Controversial1	[84,115]
	Intestinal microbiota	NA	Pos/Neg	[85-87]

¹Age as a marker remains controversial, and there are conflicting cases of relevant data.

POLE: Polymerase gene epsilon; LDH: Lactate dehydrogenase; NLR: Neutrophil-to-lymphocyte ratio; miRNA: Micro RNA; Pos positive: Neg negative; NA: Not applicable; ICI: Immune checkpoint inhibitor.

Table 3 Clinical trials on combination therapy or neoadjuvant therapy being conducted in the immune checkpoint inhibitor treatment of gastrointestinal tumors

Clinical trial ID	Cancer type	Study type	Phase	Number	Strategy	Ref.
NCT02918162	GC; Adenocarcinoma of the GE junction	Interventional	2	40	Pembrolizumab combined with stand of care chemotherapy regimen	[116]
NCT04948125	GC	Interventional	2	20	Camrelizumab combined with Apatinib Mesylate	[117]
NCT04196465	GC, ESCA, HCC	Interventional	2	48	IMC-001 as neoadjuvant therapy	[118]
NCT03841110	GC, CRC	Interventional	1	76	FT500 combined with Nivolumab/Pembrolizumab/Atezulizumab	[119]
NCT02903914	GC, CRC	Interventional	1/2	260	Pembrolizumab combined with Arginase Inhibitor INCB001158	[120]
NCT03259867	HCC, GC, CRC (All have liver lesions)	Interventional	2	80	Pembrolizumab/Nivolumab combined with TATE	[121]
NCT04822103	ESCA	Observational	NA	150	ICIs combined with Neoadjuvant chemotherapy	[122]

GI: Gastrointestinal; GC: Gastric cancer; ESCA: Esophageal cancer; GE: Gastroesophageal; HCC: Hepatocellular cancer; CRC: Colorectal cancer; TATE: Transarterial Tirapazamine Embolization; NA: Not Applicable; ICI: Immune checkpoint inhibitor.