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.