Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience?
Abstract
:1. Introduction
2. The Acute Phase Reaction and the Biology of CRP
2.1. The Acute Phase Reaction
2.2. The Biology of CRP
2.3. Summarizing Comment: The Acute Phase Reaction Reflects Complex Biological Mechanisms and the Acute Phase Protein Profile Will Probably Differ Both between Individual Patients and between Inflammatory Diseases
3. Proinflammatory Markers for Prognostication in Cancer Patients; Molecular and Hematological Markers
3.1. Inflammaging; Inflammation as a Part of the Aging Process
3.2. Inflammatory Markers in Solid Tumors
3.3. Inflammatory Markers in Multiple Myeloma
3.4. Proinflammatory Markers as Prognostic Biomarkers in Renal Cancer and Squamous Cell Head and Neck Cancer; the Use of Acute Phase Cytokine Profiles Rather Than Single Molecular Markers
4. The Use of Proinflammatory Markers in Cancer Patients with Immune-Mediated Complications; Studies of Graft Versus Host Disease and Cancer Immunotherapy
4.1. Graft Versus Host Disease in Patients with Hematological Malignancies Treated with Allogeneic Stem Cell Transplantation
4.2. The Use of Inflammatory Markers to Identify Responders to Anticancer Immunotherapy and/or Patients with Increased Risk of Severe Immune-Mediated Toxicity
5. Discussion
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Classification | Mediators | Altered Level During Infection |
---|---|---|
Cytokines | Chemokines | Increased levels of CCL2, CXCL8/IL8 Decreased levels of CCL5 |
Interleukins | Increased levels of IL1β, IL4, IL5, IL6, IL8, IL10 | |
Growth factors | Increased levels of G-CSF, GM-CSF, thrombopoietin | |
Immunomodulators | Increased levels of TNFα and IFNγ | |
Cytokine receptors or antagonists | Increased levels of soluble IL4Rα Increased levels of Type I and type II TNF receptors Increased levels of IL1RA | |
Soluble cell surface molecules | Soluble triggering receptor expressed on myeloid cells | Increased |
Selectins | Decreased levels of soluble E-selectin (expressed by endothelial cells), P-selectin (platelets, megakaryocytes, endothelium) and L-selectin | |
ICAM1, CD14 | Increased levels | |
Proteases | MMP10, TIMP1 | Increased levels |
Matrix molecules | Increased levels of endocan (endothelium-derived) | |
Other markers | Increased levels of phospholipase-A2, whereas levels of elastase (neutrophil marker) and neopterin (marker of monocyte activation) are not altered Decreased levels of albumin and Fas-ligand |
Characteristic | Description |
---|---|
Baseline levels | Influenced by several factors including age, gender, smoking, weight, blood pressure, lipid levels, CRP gene polymorphisms, hormone replacement therapy |
Isoforms | Native CRP is a pentameric protein. Monomeric CRP: formed by irreversible dissociation of the pentamere into monomers (206 amino acids, molecular weight 23 kDa). CRP is synthesized as monomers; the pentamere is then formed in the endoplasmatic reticulum where it is stored and from where it is released slowly at the non-inflammatory state. The pentamere is rapidly released in response to increased levels of proinflammatory cytokines. CRP can also form fibril-like structures, decameres and possibly trimers and tetramers Various CRP peptides may also mediate biological effects [28]. |
CRP releasing cells | The native isoform is mainly released by hepatocytes but can also be released by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. |
CRP release | The pentamere is formed and stored in the endoplasmatic reticulum from where it is slowly released in the absence of inflammation. CRP is rapidly released in response to proinflammatory cytokines. When the inflammatory stimulation is removed CRP levels decrease with a half-life of 18–20 h. |
CRP gene expression | IL6 is important for CRP expression but is not sufficient alone; TNFα, IL8/CXCL8, and CCL2 (MCP1) can also stimulate CRP expression. |
CRP ligands | The CRP pentamere can bind to a wide range of ligands including polysaccharides, proteins, chromatin/nuclear antigens, damaged cell membranes, apoptotic cells. |
CRP receptors | The complement receptors FcγRI (CD64), FcγRIIa (CD32), FcαRI (CD89), Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), αvβ3, and α4β1 integrins, FcγRIII (CD16), lipid rafts. |
Important pentameric CRP effects | Complement: activation of the classical complement cascade Monocytes/macrophages: polarization to the proinflammatory M1 phenotype, stimulation of phagocytosis and cytokine release, inhibition of chemotaxis, increased LDL uptake. Dendritic cells: CRP seems to be an important regulator even in the absence of an acute phase response; it can also activate monocyte-derived dendritic cells and thereby induce T cell activation [29,30]. Neutrophils: inhibition of activation and chemotaxis, stimulation of phagocytosis depending on the biological context. Endothelial cells: activation. Platelets: inhibition of activation, trafficking, and aggregation. |
Important monomeric CRP effects | Monocytes: stimulated reactive oxygen species (ROS) release. Neutrophils: induced activation/adherence/ trafficking; reduced apoptosis Endothelial cells: activation. |
CRP peptide AA 201-206 | Inhibition of neutrophil adhesion to endothelial cells; inhibition of platelet activation and capture of neutrophils [27]. |
Inflammatory Parameter | Comments/Observations |
---|---|
CRP | This is the most frequently studied proinflammatory parameter, and it has been investigated in several retrospective and prospective studies [43]. One of the available systematic reviews described the results for 271 articles [42]. Increased CRP was associated with an adverse prognosis and increased mortality in 245 of these studies, and for 80% of these studies the increased mortality was predicted in multivariate analyses. Half of the articles investigated patients with gastrointestinal or kidney malignancies. |
Albumin | A systematic review identified 31 studies including 9753 patients [43]. The frequency of patients with albumin <30 g/L varied between 20 and 50% in different studies. Meta-analyses showed significant associations between low albumin and adverse survival both when using albumin cutoff of 30 and 35 g/L. |
CRP:albumin ratio (Glasgow prognostic score) | Both the original Glasgow prognostic score and the modified Glasgow prognostic score were based on a cut-off value of <35 g/L for albumin and >10 mg/L for CRP [45]. An early review described associations between a high score and adverse prognosis both for patients with operable (28 studies, 8333 patients) and inoperable tumors (11 studies, 2119 patients); and similar associations may also be present for patients receiving chemoradiotherapy especially for colorectal and gastroesophageal cancer [45]. An updated meta-analysis of studies including patients without metastases (25 studies, 12,097 patents) showed an association between high pretreatment ratio and survival; colorectal cancer was an exception in this study [44]. |
White blood cell count | Relatively few studies have investigated this parameter, and to the best of our knowledge, no meta-analyses are available. Increased levels are seen for 20–30% of patients [43]. |
Neutrophil count | A recent systematic review and meta-analysis was based on nine publications including 2870 patients [43]. There was a significant association between granulocytosis and decreased survival. The frequency of patients with granulocytosis varied between studies (12–32%). |
Lymphocyte count | A recent review was based on 11 articles (2517 patients) [43]. The overall data showed a significant association between low lymphocyte counts and adverse prognosis. However, there was a considerable variation in lymphocyte threshold between studies. |
Monocyte count | A recent review identified five retrospective studies based on multivariate analyses including 1152 patients [43]. Monocytosis was associated with an adverse prognosis. The proportion of patients with monocytosis in these studies was above 20% and was 57% for the study with the highest proportion. |
Platelet count | A recent review identified seven studies including 2293 patients, and they observed a general association between increased platelet counts and survival [43]. The proportion of patients with thrombocythemia was between 10% and 30% in most of these studies. |
Neutrophil:lymphocyte ratio | A recent review was based on 59 articles (16,921 patients) [43]. Significant associations between increased levels and adverse prognosis (i.e., reduced overall survival) were observed both when using a threshold of 4 or 5 mg/L. The proportion of patients with CRP levels >5 mg/L was 20-50% for most studies. |
Lymphocyte:monocyte ratio | A recent review described the results for 11 publications (5043 patients) and observed a significant association between a low ratio and adverse prognosis [43]. However, different thresholds were used, but usually approximately 50% of the patients had a low ratio. |
Platelet:lymphocyte ratio | An increased ratio is relatively common in cancer patients (20–60%); single studies have described associations between this ratio and adverse prognosis but the threshold used varies considerably between studies and no meta-analyses are available [43]. |
Malignancy | Number of Patients/Studies | Observation |
---|---|---|
Breast [46] | 4502/10 | CRP: significant association between CRP and overall, disease-free and cancer-specific survival |
Osteosarcoma [47] | 397/2 | CRP: increased levels associated with adverse prognosis with reduced overall survival |
Nasopharyngeal [48] | 5215/5 | CRP: increased levels associated with adverse prognosis |
Lung cancer [49,50] | 3165/10 | CRP: high pretreatment levels were associated with poor overall survival |
1257/4 | CRP:albumin ratio: levels associated with poor overall survival in multivariate analysis. The cut-off values varied between the four studies | |
Pancreatic [51,52,53] | 685/10 | Resectable pancreatic cancer: only a trend for adverse prognosis in some of the studies |
1804/11 | Neutrophil:lymphocyte ratio: unfavorable impact on both overall and cancer-specific survival | |
3182/15 | Neutrophil:lymphocyte ratio: patients with a low ratio had better overall and progression-free survival | |
Esophageal [55] | 4551/10 | Neutrophil:lymphocyte and CRP:albumin ratios: high ratios were associated with poor overall survival |
Colorectal [56,57] | 3431/9 | CRP:albumin ratio: high ratio associated with decreased overall survival; high values also correlated with large tumor diameter and lymph node metastases |
1705/12 | CRP: increased levels associated with shorter overall and disease-free survival both for local and advanced disease | |
Urological [58] | 7490/43 | CRP: high CRP associated with reduced overall, cancer-specific, and relapse-free survival in for urological cancer. Furthermore, a review article suggests that this prognostic impact is seen both for renal cell, upper urinary, bladder, and prostatic cancer [65] |
Bladder [59,60] | 5546/34 | CRP: high levels being an independent prognostic marker in urothelial bladder carcinoma |
22,224/32 | Bladder cancer treated with radical cystectomy: decreased survival associated with high neutrophil:lymphocyte ratio, CRP and white blood cell count | |
Renal [61,62] | 14,136/47 | CRP, platelet count: increased levels associated with reduced overall and cancer-specific survival |
4100/24 | CRP: increased levels associated with higher stage, grade, overall mortality, cancer-specific mortality, and cancer progression. Decreased survival was also seen for patients with local disease at the time of diagnosis | |
Prostate [63,64] | 1497/5 | CRP: high levels associated with overall and progression-free survival 1 |
659/6 | Metastatic prostate cancer: high CRP levels associated with decreased overall survival |
Prognostic Use and Therapeutic Agent | Comments |
---|---|
Response to treatment | |
Ipilimumab [100] | Melanoma patients (n = 720): both pretreatment high absolute neutrophil count and high neutrophil:lymphocyte ratio were associated with adverse impact both with regard to disease progression and death, and with each of the two parameters the prognosis worsened (i.e., they had independent impact]. |
Ipilimumab [101] | Melanoma patients (n = 58): high pretreatment neutrophil:lymphocyte ratio was associated with reduced survival in multivariate analyses. |
Ipilimumab [102] | Melanoma patients (n = 95): both disease control and survival was associated with decreasing CRP levels as well as decreasing levels of circulating regulatory T cells and increasing absolute lymphocyte counts during treatment, i.e., 12 weeks after initiation of treatment. |
Ipilimumab [103] | Melanoma patients (n = 113): high pretreatment level of soluble CTLA4 had a favorable prognostic impact, was higher in responders to therapy, and was also associated with survival; these levels also increased during treatment. However, high levels were also associated with immune-related adverse events, especially of the gastrointestinal tract. |
Atezolizumab [104] | Advanced pulmonary cancer (n = 751 + 797): pretreatment CRP level was associated with an adverse prognosis and the most predictive biomarker for overall and progression-free survival. CRP was included in a prognostic index together with LDH, PD-L1 expression, performance status, time since metastases and metastatic site count. |
Nivolumab [105] | Metastatic renal cell carcinoma (n = 58): increased neutrophil:lymphocyte, monocye:lymphocyte and platelet:lymphocyte ratios were associated with shorter progression-free survival, and overall survival was significantly shorter for patients with increased levels of these three ratios as well as for patients with high CRP. The monocyte:lymphocyte ratio was an independent factor for progression-free survival, whereas high monocyte ratio, neutrophil:lymphocyte ratio and CRP levels were independent factors for overall survival. |
Nivolumab or pembrolizumab [106] | Non-small cell lung cancer (n = 34): samples were collected within 7 days before and 7 days after initiation of therapy. After initiation of treatment the IL6 and CRP levels increased for a subset of patients, and this subset showed an increased frequency of response to treatment and a prolonged overall survival. |
Avelumab, nivolumab, pembrolizumab [107] | Gastric/gastroesophageal cancer (n = 57): several proinflammatory markers were tested. High neutrophil:lymphocyte ratio, high CRP, and low albumin were all associated with short overall survival and were built into a prognostic nomogram. Patients with high score had a survival of only few months, patients with low score lived for more than 16 months. |
Risk of toxicity | |
Ipilimumab [103] | Melanoma patients (n = 113): high pretreatment levels of soluble CTLA4 had a favorable prognostic impact (see above) but were also associated with the risk of immune-related events, especially of the gastrointestinal tract. |
CAR-modified T cells with anti-CD19 [108] | Relapsed/refractory ALL (n = 51): the peak cytokine levels were determined during the first month after infusion, and peak levels of IL6, IL8, sIL2Rα, sIL6R, IFNγ, CCL2, CCL3, CCL4, sgp130, and GM-CSF. Later development of severe cytokine release syndrome could be predicted both in the test and validation group based on a signature including three cytokines. CRP levels during the same period were not predictive but increased during severe CRS. Another study has confirmed that CRP can serve as an indicator of severity for CRS [110]. |
Ipilimumab [109] | Melanoma (n = 140): a severe adverse event was observed for 36 patients. The authors investigated cytokine levels, white blood cell counts, and tumor burden parameters. Females showed an increased frequency of adverse event, but associations were observed between low pretherapy IL6 levels and higher overall survival as well as higher risk of adverse events. |
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Bruserud, Ø.; Aarstad, H.H.; Tvedt, T.H.A. Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience? Cancers 2020, 12, 1966. https://doi.org/10.3390/cancers12071966
Bruserud Ø, Aarstad HH, Tvedt THA. Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience? Cancers. 2020; 12(7):1966. https://doi.org/10.3390/cancers12071966
Chicago/Turabian StyleBruserud, Øystein, Helene Hersvik Aarstad, and Tor Henrik Anderson Tvedt. 2020. "Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience?" Cancers 12, no. 7: 1966. https://doi.org/10.3390/cancers12071966