T lymphocytes
T lymphocytes (T cells) are an important part of the human adaptive immune response and cellular immune response. T cells play an important role in anti-tumor immune response and are the most researched immune cells in TIME[91]. T cells consist of different subpopulations, including naïve T cells that can respond to new antigens, memory T cells that are activated from previous antigens and maintain long-term immunity, and regulatory T cells that regulate immune response[91]. It was found that the percentage of TIT in EGFR mutant NSCLC was lower than that in NSCLC without EGFR mutation, and a low percentage of TIT predicted poor prognosis[92]. Another study found that the number of CD8+CD39+T cells in EGFR mutant NSCLC patients was less than that in EGFR wild-type NSCLC patients. The study suggested that CD39+T cells were related to the good effect of the immune checkpoint inhibitor (ICI), which partly explained the poor effect of EGFR mutated NSCLC on ICI[93]. Moreover, it was found that the number of CD8+ tumor infiltrating T cells in EGFR mutant NSCLC was less than that in EGFR wild type NSCLC[94], and the proportion of PD-L1 + or PD-1 +, CD8 + T cells in CD8 + T cells were also less comparing with non-EGFR mutant NSCLC[95, 96]. This was also confirmed by an animal experiment on genetically engineered mice with EGFR mutation. The study found that the number of CD8+ TIT in mice with EGFR mutation was less than that with EGFR wild type and other driving gene mutations[97]. T cell immunoglobulin and mucin domain containing protein 3 (TIM3) is a member of the TIM family. Studies have found that the number of TIM3+T cells in the EGFR mutant NSCLC tumor is less than that in EGFR wild type tumor, and T cells with TIM3 positive consisted of CD8+T cells, CD4+T cells, and NKT cells[98].
On the comparison of before and after EGFR-TKIs treatment, the study found that the total T cells, CD4+T cells, and CD8+T cells of patients with EGFR mutation had no significant changes before and after EGFR-TKI treatment, but the ratio of CD4+/CD8+T cells increased, and the high ratio of CD4+/CD8+T cells was associated with poor prognosis[73]. Studies have found that T cell apoptosis was caused by EGFR mutation which increased the expression of PD-L1 through the p-ERK1/2/p-c-jun pathway. EGFR-TKIs prevented T cell apoptosis and inhibit tumor proliferation by decreasing the expression of PD-L1 through inhibiting the EGFR pathway[99]. Another study found that the number of Treg in EGFR mutant NSCLC was less than that in non-EGFR mutant NSCLC, because The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4+ regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8+ T cell infiltration. EGFR-TKIs can reverse this phenomenon by inhibiting EGFR signaling pathway[100]. The anti-tumor response of T cells is recognition of the tumor antigen presented by MHC-I. Studies have found that EGFR mutation decreased the expression of MHC-I through the MEK-ERK pathway. EGFR-TKIs increased the expression of MHC-I by inhibiting the EGFR pathway, and recruited T cells to the tumor. Therefore, the number of CD8+T cells in the tumor after EGFR-TKIs treatment is more than that before treatment[101].
Someone used a classification based on the PD-L1 and CD8-positive tumor infiltrating lymphocytes (TIL) statuses. The outcomes of patients with a negative PD-L1 expression and a high CD8-positive TIL count were significantly better than those with other classifications. In patients with positive PD-L1 and high CD8-positive TIL, the rate of EGFR mutation was significantly lower than that in non-EGFR mutation[102]. Moreover, for positive PD-L1 and high CD8+TIL NSCLC with EGFR mutation, the prognosis of EGFR-TKIs is poor, but this type of NSCLC is likely to respond to ICI[103, 104]. A study found that the proportion of PD-L1 positive T cells in peripheral blood of patients with EGFR mutation is less than that in non-EGFR mutation patients. However, the proportion of PD-L1+T cells in peripheral blood of patients with EGFR mutation is significantly increased after the EGFR-TKIs treatment. Moreover, PD-L1+T cells are positively correlated with the poor response of EGFR-TKIs[105]. For uncommon EGFR-mutant tumors, including G719X, L861Q, S768I, and Ex20 ins, the PD-L1 expression in tumor cells was higher than that in common EGFR mutant tumors. Moreover, the proportion of CD8+TIL in uncommon EGFR-mutant tumors was more than that in common EGFR mutant tumors. Patients with high expression of PD-L1 and abundant CD8+TIL exhibited a poor response to EGFR-TKIs, but the better response to ICI[106]. There are many studies about T cells with EGFR mutation and EGFR-TKIs resistance, and the mechanisms of EGFR-TKIs resistance are diverse. Therefore, the theapeutic strategy on T cells is one of the research directions for reversing EGFR-TKIs resistance.