2.1T cells affect prognosis and efficacy of immunotherapy in NSCLC patients
The number of circulating lymphocytes, including the proportion of and the absolute number of lymphocytes, is an important indicator of the efficacy of the body’s immune function and the degree of stress[77]. Interaction and influence each other exist between the various cells in the immune system,the appropriate ratio for immune cells in the body is an important guarantee for their function. Peterson et al explored the prognostic relevance of Treg cells in 64 patients with stage INSCLC and found that a higher proportion of Treg cells in the tumor significantly increased the risk of recurrence. Immunohistochemistry has detected Treg cells in 51% of NSCLC patients. Therefore, Treg cells can be identified as an important risk factor for postoperative recurrence of NSCLC [78]. In addition, Liu et al reported that a high Foxp3+Treg/CD8+ T cell ratio predicted poor response to platinum-based chemotherapy in advanced NSCLC. Given this apparent functional relevance of Treg cells in NSCLC, targeting Treg cells might be an interesting approach for immunotherapy of lung cancer[79].
Clinically, the absolute number of lymphocytes is much more important than the proportion. Tumors can significantly inhibit the proliferation of bone marrow cells during the developmental period, significantly decreasing the absolute number of various immune cells, including lymphocytes [80-81]. At the same time, one of the main consequences of chemotherapy and radiotherapy is damaging the bone marrow[82]. As a result, it decreases the absolute number of lymphocytes that is closely related to the prognosis and efficacy of immunotherapy[83-84]. Numerous studies have shown that low lymphocyte absolute count (ALC) is an independent negative prognostic factor for advanced malignant tumors[85]. Oh et al found that the baseline absolute lymphocyte count level is an independent prognostic factor of rectal adenocarcinoma patients receiving preoperative radiotherapy and chemotherapy in different treatment periods and follow-up periods. In one study, the absolute lymphocyte count decreased after preoperative radiotherapy and chemotherapy, reaching the lowest level at 1 month but gradually increased after the end of radiotherapy and chemotherapy[86]. Furthermore, Xia Ying et al. found that the absolute numbers but not the relative numbers of lymphocyte subsets CD3+, CD4+, CD8+, B, and NK cells were significantly damaged in NSCLC patients,and were closely related to the disease progression and progression-free survival period. And they were served as biomarkers for disease prognosis and efficacy. The work indicated that only paying attention to the proportion of lymphocyte subsets in clinic is easy to lead to clinical misjudgment [87].
T cells can also effectively reduce NSCLC by increasing their activity. IFN- γ promotes the activity of T cells by inducing the presentation of antigen-presenting cells (APCs) and upregulating the expression of MHC I / peptide complex on APCs to reactivate and induce the proliferation of antigen-specific CD8+ T cells. The activated tumor antigen-specific CD8+ T cells can recognize and secrete cytotoxic molecules to kill tumor cells[88]. Wu et al showed that Fuzheng anticancer formula effectively enhances the secretion of IFN- γ by CD8+ T cells, which is critical in clearing tumor cells[89] . CTLA-4 and PD-L/PD-lL are the most studied checkpoint pathways, and they inhibit T cell activity in different ways[90-91] . CTLA-4 regulates T cell proliferation early in immune response[92] , whereas PD-1 suppresses T cells later in immune response[93] . The immune checkpoint inhibitors including ipilimumab and tremelimumab (CTLA-4 monoclonal antibody), nivolumab and pembrolizumab (PD-1 monoclonal antibody), atezolizumab and durvalumab (PD-L1 monoclonal antibody) have opened a new era in the treatment of advanced NSCLC. Nivolumab and pembrolizumab have been approved by FDA and EMA for the second-line treatment of NSCLC[94-95] .