Background
Methods
Biomarker | Author | Year | Cancer type | Patient number | Treatment | Correlation between biomarker and irAEs | Possible hypothesis |
---|---|---|---|---|---|---|---|
CRP | Abolhassani AR [18] | 2019 | MM | 37 | Anti-PD-1 Anti-CTLA-4 | CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease. | Tumor-promoting inflammation could cause a systemic inflammatory response;CRP level was positively associated with the infiltration of CD8 + T cell and Treg cell which could activate the systemic inflammatory response. |
IL-6 | Okiyama N [19] | 2017 | MM | 22 | Anti-PD-1 | The IL-6 level was significantly increased in the patients with psoriasiform dermatitis after nivolumab treatment. | Overactivation of the immune system;Excessive release of inflammatory cytokines. |
Valpione S [15] | 2018 | MM | 140 | Anti-CTLA 4 | A lower baseline level of IL-6 was strongly associated with the development of irAEs. | ||
Blood cell count | Fujisawa Y [20] | 2017 | MM | 101 | Anti-PD-1 | The increase of WBC counts and the decrease of relative lymphocyte counts were closely related to the incidence of grade 3–4 irAEs. | Conventional blood cell counts could be a crude reflection of the body’s immune state, but the mechanism is unclear. |
Diehl A [21] | 2017 | Multiple solid tumors (lung cancer, MM, RCC, urothelial, HNSCC, Merkel cell carcinoma, colon cancer) | 167 | Anti-PD-1 | Higher baseline and increase of absolute lymphocyte and eosinophil counts after ICIs treatment were strongly associated with the development of irAEs. | ||
Nakamura Y [22] | 2019 | MM | 45 | Anti-PD-1 | The elevation of absolute eosinophil count at baseline and relative eosinophil count at 1 month might be valuable biomarkers to predicte endocrine irAEs. | ||
Cytokines | Khan S [23] | 2019 | Multiple solid tumors (lung cancer, kidney cancer, MM, head/neck cancer, liver cancer, bladder cancer) | 65 | Anti-PD-1/L1 Anti-CTLA 4 | The up-regulation of various cytokines after ICIs treatment was closely related to the occurrence of irAEs, especially the induced CXCL9, 10, 11 and 13. | Activate T cell;Excessive release of cytokines;Various cytokines have powerful pro-inflammatory activities, including stimulating immune cell recruitment, proliferation, survival, differentiation, and effector functions, and many of these cytokines (such as IL-1A, IL-1B, IL-2, IFN 2, and IL-12P70) are associated with inflammation, which is the basis of autoimmune diseases. |
Lim SY [24] | 2019 | MM | 98 | Anti-PD-1 Anti-CTLA 4 | Eleven cytokines, including G-CSF, GMCSF, Fractalkine, FGF-2, IFN-2, IL-12p70, IL-1a, IL-3 1B, IL-1RA, IL-2, IL-13, were significantly upregulated in patients with severe irAEs at baseline and early during treatment. | ||
TMB | Bomze D [25] | 2019 | Multiple solid tumors | 16,397 | Anti-PD-1 | There is a significant positive correlation between high TMB and irAEs during anti-PD-1 therapy in a variety of solid tumors | While fighting against neoantigens, T cells could also cross-react with the corresponding wild-type antigens in normal tissues, resulting in damage to normal tissues. |
sCLTA-4 | Pistillo MP [26] | 2018 | MM | 113 | Anti-CTLA-4 | Higher baseline levels of sCTLA-4 were closely associated with irAEs, especially the gastrointestinal adverse events. | Elevated levels of sCTLA-4 might block the interactions between full-length CTLA-4 expressed by autoreactive T cells and Tregs as well as B7 ligands, thus enhance the cytotoxicity of T cells and reduce the immunosuppression function of Treg cell. |
irAEs | Biomarker | Author | Year | Cancer type | Patient number | Treatment | Correlation between biomarker and irAEs | Possible hypothesis | |
---|---|---|---|---|---|---|---|---|---|
GI | The disorder of gut microbiome | Chaput N [27] | 2017 | MM | 26 | Anti-CTLA-4 | Baseline stool samples without bacteroidetes and with high levels of firmicutes were more likely to develop immune-related colitis. | Impaired metabolism of beneficial bacteria;Decreased beneficial bacteria that inhibit inflammation;Microbial-derived products trigger an innate immune response. | |
CD177 and CEACAM1 | Shahabi V [28] | 2013 | MM | 162 | Anti-CTLA-4 | CD177 and CEACAM1 were highly expressed at baseline and post-baseline in patients with GI irAEs. | CD177 and CEACAM1, as activation markers of neutrophils, are involved in immune-mediated intestinal disease. | ||
Peripheral blood mRNA expression (CCL3, CCR3, IL-5, IL-8 and PTGS2) | Friedlander P [8] | 2018 | MM | 210 | Anti-CTLA-4 | Peripheral blood gene expression characteristics (mainly CCL3, CCR3, IL-5, IL-8 and PTGS2) were closely related to the immune-related diarrhea, especially grade 2–4 diarrhea. | Up-regulated genes such as CCL3, CCR3, IL-5, IL-8 and PTGS2 are involved in inflammatory immune response. | ||
IL-17 | Tarhini AA [29] | 2015 | MM | 35 | Anti-CTLA-4 | Upregulation of IL-17 level at baseline and 6 weeks after ICIs treatment showed a noteworthy correlation with grade 3 diarrhea/colitis. | IL-17, one of the up-regulated central inflammatory cytokines in IBD, was usually inhibited by CTLA-4, but the intervention of ICIs disrupted this ecological balance. | ||
HLA allele | Hasan Ali O [30] | 2019 | NSCLC, MM | 102 | Anti-PD-1 Anti-CTLA-4 | There was a significant correlation between HLA type II variant HLA-dqb1 * 03:01 and immune-related colitis. | The presence of common antigens between the tumor and colon tissue causes misleading damage to the gastrointestinal tract by the immune system. | ||
Immune-related pneumonia | CD74 | Tahir SA [31] | 2019 | Bladder cancer, prostate cancer | 8 | Anti-CTLA-4 + Anti-PD-1 | The increase of autoantibody CD74 level after ICIs treatment was notably correlated with immune-related pneumonia | CD74 stimulates the release of inflammatory mediators;There is a common antigen between the tumor and lung; ICIs disrupts the mechanism that inhibits the inflammatory response of Th2 cells. | |
Endocrine disorder | Preexisting abnormal antibodies | Toi Y [32] | 2019 | NSCLC | 137 | Anti-PD-1 | Preexisting abnormal antibodies was independently associated with irAEs. Patients with positive RF are more likely to develop dermal irAEs, and thyroid dysfunction is more common in patients with positive antithyroid antibody. | T-cells enhance the effect of PD-1 antibody, and might in turn induce B-cells to produce autoantibodies, which will lead to the toxic accumulation effect of pre-existing abnormal autoantibodies, and finally trigger irAEs. | |
Thyroid dysfunction | Abnormal TPOAb | Gay S [33] | 2019 | NSCLC, MPM | 28 | Anti-CTLA-4 + Anti-PD-1 | There was a association between widespread thyroid hypoechogenicity, decreased thyroid volume, elevated TPOAb after ICIs treatment and thyroid dysfunction. | ICIs enhance T cell activity against antigens present in healthy tissues and increase pre-existing autoantibody levels. | |
Hypophysitis | GNAL and ITM2B | Tahir SA [31] | 2019 | Prostate cancer, MM, RCC | 9 | ICI therapy | Elevated levels of autoantibodies GNAL and ITM2B are closely related to the immune-related hypophysitis. | The qualitative difference in the autoreactive effector T cells between anti-PD-1 / PD-L1 and anti-CTLA-4 treatment; The pituitary endocrine cells themselves might express CTLA-4, making hypophysis a direct target for anti-CTLA-4 antibodies. | |
Dermatologic toxicity | HLA alleles | Hasan Ali O [30] | 2019 | NSCLC, MM | 102 | Anti-PD-1 Anti-CTLA-4 | HLA- drb1 *11:01 was observably related with itching. | The presence of common antigens between the tumor and skin causes dermatologic misleading damage. | |
IL-17 | Johnson D [34] | 2019 | MM | 3 | Anti-PD-1 | Psoriasiform dermatologic toxicity induced by PD-1 inhibitor subsided after treatment with systemic interleukin-IL17A blockade. | ICIs enhance the Th17-mediated immune response in susceptible patients. |