TABLE 3.
Main studies of circulating immune cells to predict immunotherapy in the last 5 years.
| Biomarkers | Cancer type | Number of patients | Therapy | Key findings | References |
|---|---|---|---|---|---|
| CD8+, CD4+ T lymphocytes | |||||
| Cytotoxic CD8+ effector clones | Melanoma | 131 | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | Individuals with fewer expanded CD8+ T cells and lower cytotoxicity had a shorter PFS compared with those with larger clones. | Watson et al. 94 |
| CD8+PD‐1+TILs | NSCLC | 21 | Anti‐PD‐1 therapy | PD‐1+ TILs strongly predicted response to ICIs, and correlated with increased OS and durable responses. | Thommen et al. 95 |
| CCR7‐CD45RA‐CD8+ T cells; TIGIT+PD‐1+CD8+ T cells | NSCLC | 263 | Anti‐PD‐1 therapy | Lower frequency of peripheral blood CCR7‐CD45RA‐CD8+ T cells and higher TIGIT+PD‐1+CD8+ T cells were correlated with hyper‐progression disease and inferior survival. | Kim et al. 96 |
| PD‐1+ CD8 T‐cell | NSCLC | 29 | anti‐PD‐1 therapy | After 4 weeks of treatment initiation, PD‐1+CD8 T‐cell responses were observed in 80% patients exhibiting clinical benefit, whereas 70% exhibiting progression did not display a T‐cell response. | Kamphorst et al. 97 |
| CD8 T cell, ctDNA | NSCLC | 99 | Anti‐PD‐1 therapy | Pretreatment peripheral CD8 T cell, ctDNA, and dynamic ctDNA levels are associated with DCB. | Nabet et al. 98 |
| NK cells and NKT‐like cells | |||||
| CD8+T cells, CD4+T cells | Melanoma | 20 | Anti‐PD‐1 therapy | Responding patients had higher numbers of infiltrating CD4+T cells and CD8+T cells. | Krieg et al. 99 |
| CD3+, CD4+, and CD8+ T cells, NK cells, CD8+PD1+ Eomes+T cells | NSCLC | 74 | Anti‐PD‐1 therapy | Longer OS had higher pretreatment CD3+, CD4+, and CD8+ T cells but lower NK cells. The pretreatment CD8+PD1+Eomes+T cells was significantly lower in controlled disease. | Ottonello et al. 100 |
| PD‐1+CD8 (CD28+CD27‐CD45RO+, TEEM) | NSCLC | 77 | Anti‐PD‐1 therapy | PD‐1+CD8 TEEM cells exhibited early responses after anti‐PD‐1 therapy and was associated with prolonged PFS and DCB. | Khanniche et al. 101 |
| PD‐1+CD8+ cells, PD‐1/CD8+ ratio | NSCLC | 31 | Anti‐PD‐1 therapy | High circulating NK and PD‐1+CD8+ cells combined with low PD‐1/CD8+ ratio in TILs provide a significantly prolonged PFS. | Mazzaschi et al. 102 |
| PD‐1+CD8+ T‐cells | GC | 350 | Anti‐PD‐1 therapy | Increased PD‐1+CD8+ T‐cells was prognostic for improved OS and highly correlated with Granzyme‐B+ and proliferative Ki‐67+ activity. | Choo et al. 104 |
| CD8 + TILs | NSCLC | 366 | Anti‐PD‐1 therapy | CD8 + TILs as a powerful predictor for PFS and OS. | Hashemi et al. 105 |
| CD8+CD28‐CD57+KLRG1+T cells | NSCLC | 83 | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | Higher baseline proportion of peripheral senescent CD8+CD28–CD57+KLRG1+T cells were associated with poor ORR, PFS, and OS | Ferrara et al. 109 |
| CD4+ T‐cell meta‐cluster | NSCLC | 60 | Anti‐PD‐1 therapy | CD4+ T‐cell meta‐cluster (CXCR3+CCR4−CCR6+ and CXCR3−CCR4−CCR6+ cells) were observed to be significantly correlated with PFS and OS. | Kagamu et al. 115 |
| CD4+ PD‐1+ T cells | NSCLC | 19 | Anti‐PD‐1 therapy | High peripheral CD4+ PD1+ T cells could predict longer PFS. | Inomata et al. 116 |
| CD4+T cells and CD4+/CD8+ ratio | dMMR mCRC | 41 | Anti‐PD‐1 therapy | Low levels of peripheral CD4+T cells and CD4+/CD8+ ratio could be as positive independent biomarkers for PFS and OS. | Cheng et al. 117 |
| PD‐1+CD56+ T‐cells | Melanoma | 75 | Anti‐PD‐1 therapy | Lower median frequency of PD‐1+CD56+ T‐cells was associated with superior OS and PFS. | Bochem et al. 119 |
| NK cell‐to‐Lox‐1+PMN‐MDSC ratio | NSCLC | 62 | Anti‐PD‐1 therapy | Higher NK cell‐to‐Lox‐1+PMN‐MDSC ratio was associated with responders, ORR, PFS and OS. | Youn et al. 122 |
| CD56+CD16‐PD‐1+ NK cells | NSCLC | 55 | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | CD56+CD16‐PD‐1+ NK cells showing good predictive ability to OS. | Gascon‐Ruiz et al. 123 |
| CD3+CD56+ NKT‐like cells | HCC | 25 | SBRT | Higher percentage of CD3+CD56+ NKT‐like cells was associated with higher OS. | Li et al. 131 |
| CD16+ NKT‐like cells | CRC | 87 | Surgery | CD16+ NKT‐like cells were associated with shorter DFS. | Krijgsman et al. 132 |
| CD3+CD56+NKT‐like cells | HCC | 52 | Anti‐PD‐1 therapy | CD3+CD56+NKT‐like cells were exhausted in HCC, while could be improved by PD‐1 blockade | Tao et al. 134 |
| B lymphocyte subsets | |||||
| Memory B‐cell signature | RCC, melanoma | 95 | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | Memory B‐cell signature that was significantly elevated showing clinical benefit | Varn et al. 138 |
| Intratumoral B cells | NSCLC | 891 | Anti‐PD‐1 therapy | There was a strong correlation between intratumoral B cells especially plasma cells and longer OS. | Patil et al. 140 |
| IgM+ memory B cells | NSCLC | 150 | Anti‐PD‐1 therapy | High levels percentage of peripheral IgM+ memory B cells were associated with longer PFS. | Xia et al. 142 |
| Other immune cells subsets (DCs, Treg, MDSCs) | |||||
| DCs vaccine combined anti‐CD38CpG | Lewis lung carcinoma cells, Mice | 11 | Anti‐PD‐1/PD‐L1 or anti‐CTLA‐4 | Neoantigen DCs vaccine combined with anti‐CD38 and CpG, could produce antitumor immunity against ICIs‐resistant mouse lung cancer cell lines. | Sun et al. 148 |
| PD‐1+CD4+ Treg | Breast cancer | 8 | Anti‐PD‐1 therapy | PD‐1 expression on circulating CD4+ Treg in PBC patients is reduced effectively by pembrolizumab. | Toor et al. 156 |
| Lox‐1+PMN‐MDSCs,Tregs/Lox‐1+PMN‐MDSCs ratio | NSCLC | 34, 29 | Anti‐PD‐1 therapy | Posttreatment Lox‐1+PMN‐MDSCs were diminished in responders. Tregs/Lox‐1+PMN‐MDSCs ratio≥0.39 had longer median PFS. | Kim et al. 164 |
ICIs, immune checkpoint inhibitors; PD‐1, programmed cell death protein‐1; PD‐L1, programmed cell death‐ligand 1; CTLA‐4, cytotoxic T‐lymphocyte antigen‐4; NSCLC, non‐small cell lung cancer; dMMR, deficient mismatch repair; MCRC, metastatic colorectal cancers; HCC, hepatocellular carcinoma; CRC, colorectal cancer; GC, gastric cancer; RCC, renal cell carcinoma; TIL, tumor infiltrating lymphocyte; OS, overall survival; PFS, progression‐free survival; DCB, durable clinical benefit; ORR, objective response rate; NK cells, natural killer cells; HLA, human leukocyte antigen; KLRG1, killer cell lectin‐like receptor G1; SBRT, stereotactic body radiation therapy; MDSCs, myeloid‐derived suppressor cells; PMN‐MDSCs, granulocytic/polymorphonuclear MDSCs; M‐MDSCs, monocytic MDSCs; Treg, regulatory T; cDCs, classical dendritic cells.