Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TILs) or genetically modified lymphocytes from TILs is a new effective approach, but the application of TIL immunotherapy is still limited in many solid tumors. Knowledge of the classification and function of TILs is important to develop personalized immunotherapy with TILs in non-small lung cancer (NSCLC). In this study, we show the characteristics of T-cell subsets in TILs isolated from NSCLC. CD3 CD8 CD45RA T cells outnumbered CD3 CD4 CD45RA T cells in CD45RA TILs, but it was the opposite in CD45RO TILs. Effector memory CD4 T cells predominated in CD4 TILs; about 10% of the stem cell-like memory T cells (Tscm) were detected in TILs. To further analyze their functions, we stimulated TILs from NSCLC patients by mitogens to examine cytokine production. Our data demonstrated that naive-phenotype T cells in TILs secret IFN-γ in abundance; TNF-α-producing T cells were significantly increased in TILs; there were more IL-17-expressing CD4 Tscm cells than other subtypes of CD4T cells in TILs. Our findings indicate that the CD4/CD8 naive-phenotype T cells and Tscm cells in TILs from lung cancer exhibit distinct composition and strong cytokine production. Attributes of Tscm cells from a naive-like T-cell population in TILs are the promising cell type for adoptive cell therapy in human lung cancer.

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The distribution and function of T lymphocytes in human lung cancer remain limited. In this study, we investigated the properties of human T cell subsets in the blood of non-small cell lung cancer (NSCLC) patients. We found a relatively normal level of CD4+ subsets in the blood of NSCLC patients, but CD8+ effector T cells increased and CD8+ effector memory cells declined compared to the healthy donors. To further analyze their properties, we stimulated the peripheral blood mononuclear cells (PBMCs) of NSCLC patients by mitogens to examine cytokine production. Our data suggest that both CD4+ and CD8+ naïve cells in NSCLC patients significantly reduced IFN-γ and TNF-α production. Additionally, fewer CD8+ effector cells produced IFN-γ and TNF-α in NSCLC patients than in healthy subjects. Moreover, similar results were observed for CD4+ or CD8+ memory cells in NSCLC patients for the production of IFN-γ, TNF-α, and IL-17. Therefore, our results strongly suggest that the function of CD4+ and CD8+ T lymphocytes in NSCLC patients is compromised or dysregulated. The development of vaccines and antitumor immunotherapy may be essential for the treatment of lung cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s12026-016-8882-y) contains supplementary material, which is available to authorized users.

On the basis of the autologous tumor-infiltrating lymphocytes (TILs) or genetically modified TILs for adoptive cell therapy have received more attention. Programmed cell death protein 1 (PD-1) expression on the T cells exert complex response during the tumor immune response. But the composition and function of PD-1+T-cell subsets in TILs from human lung cancer still limited. In blood and TILs from human lung cancer patients, we confirmed that PD-1 is expressed in higher levels in CD4+T-cell subsets than in CD8+T-cell subsets. To further analyze the function of PD-1+T cells in TILs, we observed the cytokine production in different T-cell subsets. We found that higher interferon-γ and granzyme B production in CD4+/CD8+PD-1+T-cell subsets in TILs than in peripheral blood mononuclear cells (PBMCs); except for PD-1+Tscm, higher tumor necrosis factor-α production was observed in PD-1+T-cell subsets in TILs than in PBMCs; the expression level of interleukin-17 were lower in PD-1++T cells in TILs than in PBMCs; and perforin expression was significantly reduced in CD4+PD-1+T cells subsets in TILs compared with peripheral blood. Clarify elucidating the composition and function of PD-1+T-cell subsets in TILs will have great value in clinical application for evaluating the sensitivity to PD-1 blockade and selecting the promising candidate T-cell subsets in TILs for combination immunotherapy in human lung cancer.

The canonical Wnt-β-catenin signaling pathway arrests the differentiation of T cells and plays an important role in phenotypic maintenance of naive T cells and stem cell-like memory T cells in human peripheral blood, but its effect on tumor-infiltrating lymphocytes (TILs) from non–small cell lung cancer is little known. In this study, we showed that glycogen synthase kinase-3β inhibitor TWS119 has different effects on CD4+ and CD8+ T cells in TILs. TWS119 preserved the expansion of naive T cell and CD8+ stem cell-like memory T cells, and induced CD8+ effector T-cell proliferation in TILs. To further determine whether TWS119 impaired the effector function of TILs, TILs were stimulated with polyclonal stimulation, IL-2 and IFN-γ production were detected. Our data showed that TWS119 does not affect the production of IFN-γ in TILs compared with the control group; whereas TWS119 inhibited IFN-γ secretion of T cells from healthy donor. IL-2 production in CD4+ central memory T cells and CD4+ effector memory T cells from TILs was significantly increased with the TWS119 treatment; TWS119 also promoted the secretion of IL-2 in all cell subsets of CD8+ TILs. These findings reveal that TWS119 has a distinct effect on the proliferation and cytokine production of TILs, and provide new insights into the clinical application of TILs with TWS119 treatment for the adoptive immunotherapy.