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In recent years, immunotherapy has achieved remarkable results. Many clinical studies have proved that immunotherapy can improve the prognosis of tumor patients and significantly prolong the survival of patients. At the same time, the exploration of immunotherapy biomarkers has also become a hot spot in immunotherapy research. Biomarkers can help determining and predicting the effectiveness of treatments and also play an important role in guiding clinical drug use.
Although inhibitors of CTLA-4 and PD-1 have achieved impressive success in the treatment of various cancer types, only a part of patients obtain clinical benefit. Recently, it is demonstrated that the efficiency of immune checkpoint inhibitors is affected by a cluster of factors or biomarkers involving in host germline genetic, tumor genetics, features of tumor microenvironment, gut microbiome and etc. Currently, the markers used to predict the efficacy of immune checkpoint inhibitors are as follows:
PD-L1 is rarely expressed in normal tissues, but PD-L1 is highly expressed in various tumor cells, such as lung cancer, malignant brain tumor, melanoma, gastric cancer and pancreatic cancer. Moreover, PD-L1 can also be expressed in myeloid cells in the tumor micro-environment. Studies have been reported that expression of PD-L1 in tumor tissues is closely related to the clinical response of patients with different tumor types. Therefore, the predictive effect of PD-L1 expression in tumor tissues on clinical efficacy and its feasibility as a biomarker for screening patients have received extensive attention.
TMB refers to the number of somatic mutations in the tumor genome after removing germline mutations. The higher the tumor TMB, the more neoantigens will be produced by tumor cells resulting in stronger T cell response and anti-tumor response. TMB expression is highest in melanoma, lung cancer, bladder cancer and gastrointestinal tumors. Besides PD-L1, TMB gradually become a potential marker to predict the efficacy of immune checkpoint therapy. Though TMB has been applied in tumor clinical therapy, there are still many problems of TMB as a predictive marker. For example, the cost of TMB detection is still higher than that of PD-L1 detection because it relies on gene sequencing. Testing standards of different platforms are not uniform. The storage time of specimens also has a certain impact on the TMB result judgment. Along with the approval of NGS panel, TMB detection will gradually be applied in clinical practice. When TMB is applied in specific clinical practice, whether ctDNA can be used to detect TMB is also a problem to be considered in the future, if the sample size of tissue is insufficient.
Microsatellite high instability (MSI-H) and mismatch repair functional defect (dMMR) represent for two different detection methods, but they perform very similar clinical guidance. MSI-H can be considered as equivalent to dMMR. If the patient's tumor tissue lesion is detected as MSI-H, or dMMR, it means that the somatic cells are over-mutated and more new antigens are expressed by tumor cells, which makes the tumor cells easy to be recognized by the immune system, thus activating the opportunity to play a killing role.
Tumor infiltrating lymphocytes (TIL) itself can be used as an immune therapy. When tumor tissues are surgical resecting, usually most of cells are tumor cells, but there are also a small number of lymphocytes in the tissues. Scientists can amplify lymphocytes in these tumor tissues with various culture methods. TIL cells will be isolated and amplified from the tumor tissues after surgery. The amplified cells are mainly CD4+ and CD8+ T cells, then TIL cells will be cultured in vitro for a period of time to be transplanted back into the patient for anticancer. Since the function of PD-1 / PD-L1 inhibitors requires the participation of lymphocytes near the tumor cells, abundance TIL can be used as a marker to predict the efficacy of PD-1 / PD-L1 inhibitors, which is usually achieved by using immunohistochemistry to assess the infiltration of CD8+T cells in tumor tissues. CD28, as a signal of co-stimulatory factor, is also paid attention to in the cancer immunotherapy. A higher proportion of CD28+ in TIL cells generally indicates a greater likelihood of a response to treatment, which can also be detected by immune-histochemistry. CD39 is a molecule associated with chronic immune cell stimulation and is typically upregulated in many malignant solid tumors. The TIL of CD8+, CD39+ is consistent with the continuous stimulation characteristics of chronic antigen, indicating that the activity of this kind of TIL is inhibited. However, its anti-tumor ability still exists. PD-1 / PD-L1 inhibitor can just remove this kind of inhibition, only external forces are able to remove its anti-tumor ability. The higher the proportion of CD39+ in CD8+ TIL, the more likely PD-1 / PD-L1 will work in anti-tumor process. Therefore, CD39+ is also a marker with great potential.
Biomarkers can help determining and predicting the effectiveness of treatment. PD-L1 and dMMR/ MSI-H are two immunotherapeutic biomarkers that have already entered clinical practice at present. New predictive markers for the efficacy of PD-L1 / PD-L1 inhibitors, such as TMB, TILs and POLE, need more clinical research evidence to support its functions. Moreover, the exploration of biomarkers for liquid biopsy also provides a broader space in the immune checkpoint biomarker filed in the future.
