The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients
Abstract
:1. Introduction
2. Predictive Biomarkers of Response Related to the Tumor
2.1. PD-L1 Expression on Tumor Cells
2.2. MHC I and II
2.3. Mutational and Neoantigen Load
2.4. Liquid Biopsy
3. Predictive Biomarkers Related to the Host Immune System
3.1. Immune Regulatory Molecules
3.1.1. LDH, CRP, and S100B
3.1.2. Cytokines
3.1.3. Soluble Checkpoint Molecules
3.2. Peripheral Blood Biomarkers
3.2.1. Total Cell Count and Ratios
3.2.2. MDSCs
3.2.3. Tregs
4. Predictive Biomarkers Related to the Host Gut Microbiota
4.1. The Effects of Gut Microbiota on Anti-CTLA-4 Therapy Efficacy
4.2. The Effects of Gut Microbiota on Anti-PD-1 Therapy Efficacy
4.3. The Effects of Gut Microbiota on Combined Therapy with Anti-PD-1 and Anti-CTLA-4 Abs
Biomarker | Treatment | Results (Correlation with Clinical Benefit or Response) | References |
---|---|---|---|
Tumor PD-L1 expression | Nivolumab | PD-L1⁺—better objective response | [21] |
Nivolumab/pembrolizumab | PD-L1⁺—better objective response, | [136] | |
Pembrolizumab | PD-L1⁺—better response rate, PFS and OS | [27] | |
Nivolumab + ipilimumab | Low PD-L1⁺—better survival outcome | [28] | |
Tumor MHC I/MHC II expression | Anti-PD-1/anti-PD-L1 | High MHC II expression—improved clinical response, longer PFS and OS | [38] |
Ipilimumab/nivolumab | Reduced MHC I expression—worse OS, lack of clinical response >1% MHC II expression—complete or partial response, stabilization | [40] | |
Mutational load, neoantigen load | Ipilimumab/tremelimumab | >100 somatic mutations—clinical benefit of responders MHC I neoantigen response and survival | [46] |
Ipilimumab | >100 mutation load and high neoantigen load—better clinical benefit | [47] | |
Anit-PD-1 | Elevated mutational load—longer median PFS and OS | [38] | |
Pembrolizumab/nivolumab | High mutation load—prolonged OS | [49] | |
ctDNA | Nivolumab/pembrolizumab | Pre-treatment undetected ctDNA—improved OS Decrease of ctDNA on-treatment—better PFS and OS | |
Ipilimumab, nivolumab, pembrolizumab, ipilimumab + pembrolizumab | Low pre-treatment ctDNA, on-treatment decrease of ctDNA—better response, prolonged PFS | [52] | |
Anti-PD-1 | Pre-treatment undetected ctDNA—better PFS and OS Pre-treatment or early on-treatment > 500 ctDNA copies—poor clinical outcome | [53] | |
Total cell count and ratios | Ipilimumab, nivolumab Ipilimumab + nivolumab | High NLR ratio—worse OS | [102,103,104,105,106,107] |
Nivolumab | >30% increase NLR ratio on-treatment—lower OS | [108] | |
Nivolumab | <4000/µL ANC, ≥1000/µL ALC on-treatment—increase OS | [70] | |
Ipilimumab | >1.35-fold increase ALC on-treatment—longer OS | [64] | |
Ipilimumab, pembrolizumab, nivolumab + ipilimumab | Elevated AEC on-treatment—better OS | [18,107,109] | |
Mo-MDSCs | Ipilimumab | Elevated mo-MDSCs—non responders, worse survival Decrease mo-MDSsC on-treatment—increased OS, higher probability of benefit from therapy | [109,113,114,115] |
Tregs | Ipilimumab | Low Tregs—favorable outcome, better OS | [113] |
Nivolumab adjuvant therapy | Low Tregs—no relapse | [117] | |
Ipilimumab | Decrease Treg son-therapy—disease control, better OS | [68] | |
Ipilimumab neoadjuvant | Increase Tregs—improved PFS | [118] | |
Nivolumab | Increase Tregs—responding | [119] | |
Cytokines | Nivolumab | High pre-treatment IFN-γ, IL-6, IL-10—response Decrease IFN-γ, IL-6, IL-10—no response | [74] |
Nivolumab | Elevated pre-treatment IL-6—irAE occurrence | [75] | |
Anti-CTLA-4 + anti-PD-1 | Elevated G-CSF, GM-CSF, Fractalkine, FGF-2, IFN-α2, IL-12p70, IL-1a, IL-1B, IL-1RA, IL-2 and IL-13—irAE occurrence | [76] | |
Soluble checkpoint molecules | Nivolumab | High sPD-L1—shorter OS, worse response | [88] |
Ipilimumab/pembrolizumab | High sPD-L1—worse prognosis Elevation sPD-L1 on-treatment—partial response | [81] | |
Pembrolizumab | High pre-treatment exoPD-L1—no response, poor clinical outcome >2-fold increase on-treatment—better PFS and OS in responders | [92] | |
Ipilimumab/anti-BRAF + anti-MEK | Elevation exoPD-L1 on-treatment—progression | [93] | |
Ipilimumab | High sCTLA-4—favorable clinical outcome, low death rate | [96,97] | |
Ipilimumab | High sCD25—poor outcome, worse OS | [99] | |
LDH | Ipilimumab Nivolumab/pembrolizumab Nivolumab + ipilimumab | Elevated LDH—worse outcome, shorter OS | [61,62,63,64,65] |
CRP | Ipilimumab | decrease CRP—response, stabilization and survival | [68,69] |
Anti-PD-1 | elevated LDH—poor OS | [70] | |
S100B | Pembrolizumab Nivolumab + ipilimumab | Elevated S100B—impaired OS | [63] |
Selected bacterial species | Anti-CTLA-4 | B. thetaiotaomicron, B. fragilis, Burkholderiales—antitumor response | [127] |
Ipilimumab | F. prausnitzii and bacterial load—beneficial clinical outcome, longer PFS and OS | [128,129] | |
Ipilimumab | Bacteroides spp.—poor clinical outcome | [128,129] | |
Anti-PD-1 | A. muciniphila, E. hirae, Faecalibacterium spp., Bifidobacterium spp., C. aerofaciens, E. faecium, K. pneumoniae, V. parvula, P. merdae, Lactobacillus spp., D. formicogenerans—antitumor responses | [130,131,132,134] | |
Anti-PD-1 | Bacteroidales, R. obeum, R. intestinalis—poor clinical outcome | [131,132] | |
Combined ICI therapies | B. caccae, F. prausnitzii, B. thetaiotaomicron, H. filiformis, C. eutactus, P. stercorea, S. sanguinis, S. anginosus, L. bacterium 3 1 46FAA—beneficial clinical outcome | [134,135] | |
Combined ICI therapies | B. ovatus, B. dorei, B. massiliensis, R. gnavus and B. producta—poor clinical outcome | [135] | |
Microbial metabolites | Ipilimumab | Elevated serum levels of propionate and butyrate—poor clinical outcome | [129] |
Nivolumab/pembrolizumab | elevated fecal SCFAs, i.e., acetic, propionic, butyric, and valeric acid and plasma isovaleric acid—response to therapy and longer PFS | [133] |
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Tomela, K.; Pietrzak, B.; Schmidt, M.; Mackiewicz, A. The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients. Life 2020, 10, 219. https://doi.org/10.3390/life10100219
Tomela K, Pietrzak B, Schmidt M, Mackiewicz A. The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients. Life. 2020; 10(10):219. https://doi.org/10.3390/life10100219
Chicago/Turabian StyleTomela, Katarzyna, Bernadeta Pietrzak, Marcin Schmidt, and Andrzej Mackiewicz. 2020. "The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients" Life 10, no. 10: 219. https://doi.org/10.3390/life10100219