With the advent of the era of tumor immunity, significant progress has been made in the treatment of cancers. In recent years, immune checkpoint inhibitors have become an effective treatment option and means for the treatment of cancer (Ferlay et al., 2015). Programmed death ligand 1 (PD-L1) is an immune checkpoint protein expressed on cancer cells or cancer infiltrating immune cells. PD-L1 binds to the programmed death 1 (PD-1) receptor on activated T cells and induces tumor immune escape by down regulating the function of antitumor T cells (Alexandrov et al., 2013; Brahmer et al., 2015). Therefore, inhibition of PD-1/PD-L1 pathway can induce immune response to cancer by restoring T cell activity (Moore et al., 2020).

Immune checkpoint inhibitors (ICIs) refer to antibodies against PD-1/PD-L1, which block the inhibition signal mediated by PD-1/PD-L1 (Dong et al., 2017). Many clinical trials involving patients with cancer tumors have shown that ICIs can achieve better survival outcomes than standard chemotherapy (Ozaki et al., 2020).

Tumor mutation load has been considered as a potential marker of cancer response to ICIs. High mutation load may be related to the increase of new antigens recognized by T cells to increase antitumor T cell response (Dong et al., 2017). KRAS, EGFR or TP53 are the most common mutated oncogenes in cancer (Dong et al., 2017). However, it is unclear whether the efficacy of ICIs in cancer patients is related to KRAS, EGFR or TP53 single gene mutations. We conducted this meta-analysis to investigate whether KRAS, EGFR or TP53 single gene mutation status affects the survival benefits of ICIs in cancer patients.

Systematically search the domestic and foreign literature on the efficacy of ICIs in cancer patients and KRAS, EGFR or TP53 single gene mutations, and evaluate whether KRAS, EGFR or TP53 single gene mutations affect the survival benefits of ICIs in cancer patients.

A large number of research data show that the emergence of immune checkpoint inhibitors has significantly affected the clinical treatment strategies of most cancer subtypes, especially non-small cell lung cancer, renal cell carcinoma, melanoma and so on. Programmed cell death-1 (PD-1) inhibitors, such as neruzumab or pemilizumab, and programmed cell death ligand-1 (PD-L1) inhibitors, such as atezolizumab, significantly improved progression free survival (PFS) and overall survival (OS) in cancer patients. Compared with platinum based standard first-line chemotherapy or docetaxel based second-line chemotherapy, excellent disease control time is achieved (Borghaei et al., 2015; Le et al., 2017).

Some studies have shown that tumor mutation burden (TMB) can predict the potential activity of immunotherapy in a variety of tumor types, including NSCLC, RCC, etc. (Song et al., 2020). By producing damaged cell proteins recognized as new antigens by immune cells, the resulting genetic instability can enhance the immunogenicity of tumors, so as to optimize the antitumor cytotoxicity of T lymphocytes recovered by ICIs treatment. For example, in colorectal cancer, mismatch repair status predicts the clinical benefit of anti-PD-1 antibody pamumab (Van Allen et al., 2015). In non-small cell lung cancer, a mutation feature associated with smoking predicts anti-PD-1 efficacy (Hollern et al., 2019). In melanoma, TMB and neoantigen load predict patients’ response to CTLA-4 treatment (Pauken et al., 2016). The presence of CD8 + T cells and the expression of immune checkpoint genes such as PD-1 ligand (PD-L1) and CTLA-4 can also predict the efficacy of ICIs (Wang et al., 2019). These data show that TMB has a significant effect on predicting the response of ICIs, and it is clinically needed.

KRAS is a guanine nucleotide binding protein that regulates the mitogen activated protein kinase (MAPK) pathway. When it is activated, it promotes downstream signaling pathways, leading to cell growth and proliferation (Nagasaka et al., 2020). KRAS mutation rate in patients with non squamous NSCLC is 20–30% (Nagasaka et al., 2020). So far, there is no therapy for KRAS mutation. Although some targeted drugs (such as G12C inhibitors) are being evaluated in clinical trials, the effective drug targeting of KRAS mutation is also an unprecedented challenge. By studying the correlation between KRAS mutation status and TMB, it was found that TMB was associated with tumor immunogenicity and greater survival benefit of ICIs treatment (Adderley et al., 2019). Recent studies reported that compared with chemotherapy patients, OS and PFS were improved in patients with KRAS mutant NSCLC after ICIs treatment, and KRAS mutant tumors showed stronger PD-L1 expression and T cell infiltration (Adderley et al., 2019). Epidermal growth factor receptor (EGFR) mutation is a good predictor of the efficacy of EGFR tyrosine kinase inhibitors. EGFR mutation is common in cancer, especially in non-small cell lung cancer. EGFR mutations are found in 32% of non-small cell lung cancer cases worldwide, of which 39% of tumors occur in Asian ethnic groups and 17% in Caucasian ethnic groups (Zhang et al., 2016). The prevalence of EGFR mutation in lung adenocarcinoma is high; 51% of East Asian lung adenocarcinoma patients have EGFR mutation (Shi et al., 2014). The high prevalence of EGFR mutations makes it more important to evaluate whether EGFR mutations are really negative predictors of PD-1/PD-L1 efficacy. The prognostic role of tumor suppressor gene TP53 mutation in predicting the efficacy of ICIs is highly controversial. An early study (Xiao et al., 2018) showed that TP53 mutation was associated with relatively short PFS and shorter OS in 110 patients receiving CTLA-4 blocking treatment. However, inconsistent results were observed in another group of patients with non-small cell lung cancer treated with PD-1 + CTLA-4 block. The study found that TP53 mutation was enriched in responders, suggesting that TP53 may be related to the enhanced response of combination therapy. In addition, Dong et al. (Ozaki et al., 2020) confirmed that patients with lung adenocarcinoma had a relatively good response to TP53 mutation when treated with PD-1 inhibitors, suggesting that TP53 may help to guide the decision of clinical use of ICIs.

In addition, many cancers show different patterns of genomic changes. In the development of cancer, KRAS, as a driving oncogene, has a high mutation frequency. However, it has recently been found that cancers with KRAS mutations also express TP53 mutations. TP53, as a core cancer suppressor gene, encodes p53 protein in humans and mice to prevent mutations in a stable state. Notably, TP53 mutations drive lung cancer, with a higher frequency of TP53 mutations than EGFR or KRAS mutations in LUAD. Studies have shown that tumors with co-mutations of KRAS/TP53 usually show significant upregulation of PD-L1 expression and accumulation of tumor-killing T cells. In this regard, in addition to PD-L1 expression, TP53 mutations will hopefully guide the clinical application of immune checkpoint blocking therapy for KRAS mutated lung adenocarcinoma. However, the prognostic effect of TP53 mutation on EGFR mutant lung cancer is controversial. TP53/EGFR co-mutations may be associated with treatment resistance and shorter survival in lung cancer patients, the study showed. On the other hand, Labbe et al. (Zhang et al., 2019) studied 105 egFR-mutant NSCLC patients, and among the patients undergoing surgery, progressionfree survival (HR 0.99, 95%CI: 0.56-1.75) and overall survival (OS, HR 1.39, 95%CI: 0.70-2.77) was unrelated to TP53 status. Therefore, considering these controversial findings and evaluating the prognostic value of TP53/EGFR co-mutations in lung cancer will also be the focus of our subsequent studies.

In this meta-analysis, we investigated whether the survival benefits of ICIs in cancer patients vary according to KRAS/EGFR/TP53 single gene mutation status. We found that the PFS and OS of patients with KRAS/EGFR/TP5 single gene mutant tumors were significantly improved and the degree of improvement was different when treated with ICIs. TP53 mutant showed a better effect than KRAS mutation and EGFR mutation. These results suggest that KRAS/EGFR/TP53 single gene mutation status may be a potential biomarker of the survival benefits of ICIs. In the future, ICIs may play an important role in the treatment of early cancer. After radiotherapy and chemotherapy, immunotherapy has become the standard treatment of cancer, regardless of its mutation status. Even in the early stages of the disease, molecular characteristics will become the basis to determine the optimal treatment strategy and its combination with local regional treatment, especially in oncogene addiction diseases.

Considering the limited amount of data based on this meta-analysis, further research is needed to evaluate the effect of KRAS/EGFR/TP53 single gene mutation on the efficacy of ICIs in cancer patients. We also expect that the latest progress of next-generation sequencing technology will help to identify more accurate biomarkers and bring clinical benefits to ICIs immunotherapy.