Table 1 |.
Potential role of biomarkers associated with host–microbiota interactions in immuno-oncology
| Biomarker | Rationale | Role in routine oncology |
|---|---|---|
| Standard use | ||
| PD-L1 | Tumour PD-L1 expression assessed by IHC positively correlates with CD8+ T cell infiltrates and ICI efficacy in cancer174 | FDA approval of PD-L1 IHC as a companion diagnostic biomarker for anti-PD(L)1 antibodies, in metastatic or advanced-stage NSCLC, cervical cancer, HNSCC, ESCC, TNBC and urothelial carcinoma175 |
| MMR | MMR deficiency (assessed by tumour DNA sequencing) associated with TMB, CD8+ TILs and clinical efficacy176 | FDA approval for endometrial carcinoma and solid tumours175,176 |
| TMB | High TMB (≥10 mut/Mb) associated with improved survival in NSCLC, melanoma and HNSCC, but not in ESCC, gastric cancer, CRC, urothelial carcinoma, brain cancer, unknown primary tumours or other tumours after stratification based on MMR and polymerase δ status177–179 | FDA approval, available in solid tumours, for example with FoundationOne CDx175,180 |
| LIPI | Association between the neutrophil-to-lymphocyte ratio and LDH in blood181; association with gut dysbiosis (alpha and beta diversity)182 | Investigator choice for routine implementation |
| IL-8 | Plasma, PBMC and tumour IL-8 levels at baseline or on treatment are surrogates for intratumoural high densities of myeloid infiltrates and neutrophils that predict reduced efficacy (when high or increased) of ICIs in metastatic melanoma, NSCLC, urothelial carcinoma and RCC in retrospective phase III trials183,184 | Plasma IL-8 (≥23 pg/ml) determined by ELISA, at baseline and on treatment in metastatic melanoma, NSCLC, urothelial carcinoma and RCC; prospective validation ongoing |
| Gut-derived biomarkers (from microbiota and epithelia) | ||
| Microbiome | Baseline faecal bacteria and archaea alpha diversity, richness and specific taxonomic composition associated with ICI clinical outcome26,38–40,42,44,91,96,97,100,105,125,126, as assessed by 16S rRNA sequencing, MGS or targeted-PCR on specific taxa | Shown in retrospective studies of CD19-targeted CAR T cells, and of ICIs in neoadjuvant and metastatic cancers; prospective validation pending (NCT04567446, ANR-21-RHUS-0017) |
| sCD14, sST2, LBP and sMAdCAM-1 | Serum markers of leaky gut associated with cancer, and stress ileopathy25,26,42, and dysbiosis21 | Biological and clinical relevance of ICI resistance shown in retrospective studies in NSCLC, RCC and urothelial carcinoma for sMAdCAM-1 only21 |
| Exfoliome | Mammalian DNA contamination in stool MGS and/or non-invasive stool transcriptomics as surrogate markers of pathogenic host–commensal crosstalk40 | Association with endotoxaemia and dysbiosis40 |
| Microbiota-derived metabolites | ||
| SCFAs | High faecal levels of acetate, propionate, butyrate and valerate, and high blood levels of isovalerate associated with improved outcomes in ICI-treated patients144 | Controversial findings145; prospective validation required; might support the recommendation of high-fibre-based diet to increase ICI efficacy53 |
| Inosine | During ICI or CpG immunostimulation, inosine exhibited a T cell intrinsic IL-12Rb-dependent stimulatory capacity167 | Translation of these findings in mouse models to humans awaited |
| Kyn to Trp ratio, I3A and 3-IAA | Higher plasmatic Kyn to Trp ratio measured by LC–MS is associated with early progression and reduced OS to ICIs in several cancer types151,152; enrichment of Trp pathway in five gut-associated phyla154; 3-IAA associated with response to chemotherapy in PDAC185 | Controversial findings186; might support Trp-enriched diet, or I3A or 3-IAA-based prebiotics in combination with ICIs155,185 |
| L-Arg | Low baseline blood L-Arg levels associated with worse clinical outcomes in ICI-treated patients159,160 | To be validated in prospective cohorts |
| Bile acids | Preclinical studies associated bile acids and gut microbiota composition with cancer immunosurveillance19 and ICI efficacy162; modulation of bile acid composition after FMT or after anti-PD-1 antibody therapy in responders128 | Further studies required to assess the clinical relevance of bile acids during immunostimulation |
| TMAO | TMAO induces a type I interferon fingerprint in tumoural macrophages; CutC-encoding commensals associated with response to anti-PD-1 antibodies in melanoma170 | Prospective validation required to address whether choline-enriched diet promotes ICI efficacy170 |
| Immune responses directed against commensals or pathobionts | ||
| Bacteria-specific memory T cells | Reactivities towards commensals, such as Enterococcus hirae, Bacteroides fragilis, Akkermansia muciniphila or faecal bacteria, predict response to chemotherapy126, ICIs42,125 or FMT128 | Prospective validation required |
| IgA and IgG titres against commensals | Blood or faecal IgA and IgG bound to bacteria (detected by flow cytometry) are associated with gut microbiota composition and ICI response113,116,118,187 | Prospective validation of clinical relevance needed |
| TLS and TFH | Association between intratumoural Escherichia coli, maturation of TLS, on-treatment increase in serum CXCL13, E. coli-specific IgG titres and response to neoadjuvant ICI in urothelial carcinoma119,120 | Cause–effect relationship between tumoural bacteria and TLS not established |
| Intratumoural infection by pathobionts, antigen mimicry and adjuvanticity | Bacterial MHC class I and class II epitopes presented at tumour membrane activate TILs188; molecular mimicry between oncogenes or tumour antigens, and phage or bacterial peptides123,124; immunogenicity of outer membrane vesicles and genetically modified bacteria123,189–191 | Ongoing clinical trials (NCT04116658, NCT04187404) |
16S rRNA, 16S ribosomal RNA; 3-IAA, indole-3-acetic acid; L-Arg, L-Arginine; CAR, chimeric antigen receptor; CRC, colorectal cancer; ELISA, enzyme-linked immunosorbent assay; ESCC, oesophageal squamous cell cancer; FMT, faecal microbiota transplant; HNSCC, head and neck squamous cell carcinoma; I3A, indole-3-aldehyde; ICI, immune-checkpoint inhibitor; IHC, immunohistochemistry, Kyn, kynurenine; LBP, LPS-binding protein; LC–MS, liquid chromatography–mass spectrometry; LDH, lactate dehydrogenase; LIPI, Lung Immune Prognostic Score; MGS, shotgun metagenomics sequencing; MMR, DNA mismatch repair; NSCLC, non-small-cell lung cancer; OS, overall survival; PBMC, peripheral blood mononuclear cell; PDAC, pancreatic ductal adenocarcinoma; RCC, renal cell carcinoma; SCFA, short-chain fatty acid; TFH, T follicular helper cell; TIL, tumour-infiltrating lymphocyte; TLS, tertiary lymphoid structure; TMAO, trimethylamine N-oxide; TMB, tumour mutational burden; Trp, tryptophan; sCD14, soluble CD14; sMAdCAM-1; soluble mucosal addressin cell adhesion molecule 1; sST2, soluble IL-1 receptor-like 1; TNBC, triple-negative breast cancer.