Table 2 The possible mechanism of biomarkers in HPD after ICB therapy
From: The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy
Biomarker | Description | Mechanism |
|---|---|---|
Tumor cell biomarkers | ||
 MDM2 family | MDM2 is overexpressed by amplification | Hyperexpression of MDM2 might be triggered by amplification during ICB therapy through IFN-γ, especially JAK-STAT signaling that increases IRF-8 expression. Overexpression of MDM2 due to amplification associated with metastasis and formation of the transfer site. |
 EGFR mutation | EGFR gene mutations and protein overexpression | EGFR mutation is related to upregulated expression of PD-1, PD-L1, CTLA-4 and immunosuppressive cells, such as Treg cells and macrophages; EGFR gene mutations and protein overexpression are associated with cancer growth through activation of downstream pathways: the MAPK pathway, PI3K/AKT pathway and JAK/STAT pathway |
 BRCA2 mutations | Enrichment for BRCA2 mutations | As the LOF mutation, BRCA2 mutations might impair dsDNA break repair mechanisms and homologous recombination, which might induce specific mutational features related to anti-PD-1 responsiveness. Conversely, it is related to HPD. |
 MMR/MSI | MMR deficiency leads to accumulation of mutations | More potential neoantigens were produced by the accumulation of mutations of MMR deficiency, which upregulated TIL density, increased TMB, elevated PD-L1 expression, and induced a greater immune response to the tumor. Conversely, it is related to HPD. |
 TMB | An independent biomarker that is predictive of ICB outcomes | The accumulation of genomic alterations generates neoantigens at the protein level, which may be recognized by the patient’s immune system as nonself or foreign antigens. Neoantigenicity is measured by TMB. Conversely, it is related to HPD. |
Tumor microenvironment biomarkers | ||
Immunological cells | ||
 Treg cells | Activated Treg cells enhance suppressive activity | Hamper activation of effector T cells, resulting in more Treg cells; inhibit IL-2 release and absorb it; many factors such as adenosine and IDO are upregulated |
 Exhausted T cells | Progressive increase in exhausted T cells | Upon blocking of PD-1, the compensatory immune-checkpoints (PD-1, TIM3, LAG3 and TIGIT) might overexpressed and regulate local immune suppression and escape |
 Dendritic cells | Generating the anti-tumor response by T cells | The response of T cells could be inhibited through PD-L1 by DCs; cytokines, such as TGF-β, IL-6 and IDO, inhibit the activity of DCs, thus having a negative regulatory effect on T cells |
 MDSCs | High frequencies of MDSCs related to ICI resistance | Impair the activity of effector T cells, induce expansion of Treg cells, reduce the functions of NK cells, secrete cytokines (IDO, VEGF, MMP9 et al.) |
 M2 macrophages | Triggering of clustered M2 TAMs | The response of T cells could be inhibited through PD-L1 by M2 TAMs; the binding between specific immunophenotypes through ICB and FcR might trigger clustering of M2 TAMs, which could induce more aggressive protumorigenic behavior by upregulating functional reprogramming in M2 TAMs |
Nonimmunological cells | ||
 CAFs | Related to immunosuppression | Recruit monocytes that encompass immunosuppression and enhance the motility of tumor cells; induce differentiation of M1 TAMs into M2 TAMs; inhibit T cell immunity through neutrophils |
Cytokines and inflammatory factors | ||
 IFN-γ | Loss of sensitivity to IFN-γ | Molecules in the IFN-γ pathway, including IFNGR1/2, JAK1/2, STAT1, PI3K-AKT, and IRF1, were mutated or downregulated, thus decreasing the expression of PD-L1 |
 Other compensatory immune checkpoints in T cells | PD- L2/soluble PD-1 | PD-1 blockade can induce inhibition of T cells through the combination of PD-1 and PD-L2; soluble PD-1 fusion protein might inhibit the activity of bone marrow-derived DCs and increase the secretion of IL-10 |
Laboratory biomarkers | ||
 ANC/CRP | ANC and CRP were significantly higher in the HPD group than in the non-HPD group | The upregulation of the ANC might be used to reflect the release of premature myeloid cells from the bone marrow, such as MDSCs, which are related to tumor invasion and metastasis. MDSC counts are also positively correlated with CRP levels |
Clinical indicators | ||
 Regional recurrence in an irradiated field | RSCCHN patients with regional recurrence had HPD | Radiotherapy might be related to ICB treatment failure by regulating the tumor microenvironment through a decrease in TILs and the main cytokines and an increase in PD-L1 transcripts |
 More than two metastatic sites | HPD was more frequent in patients who had more than two metastatic sites of advanced NSCLC | More aggressive tumor phenotypes might be related to HPD |
 Age ≥ 65 | More patients of advanced age (≥65) had HPD than younger patients. | Immunosenescence: age-related thymic atrophy connected with lowing the T cell immunity, which plays a key role in autoimmune disease, infection, and tumors |