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Page 4 of 15                      Sawayama et al. J Cancer Metastasis Treat 2018;4:10  I  http://dx.doi.org/10.20517/2394-4722.2017.79


               T-bet+ lymphocytes is a significant advantage to survival; moreover, the amount of CD3+ TILs in the intra-
               tumoral compartment is the most significant prognostic marker [pooled hazard ratio (HR) = 0.52; 95%
               confidence interval (CI) = 0.43-0.63; P < 0.001]. CD4+ TILs are not statistically associated with prognosis.
               FOXP3+ TILs show bidirectional prognostic roles, which have a positive effect in the intra-tumoral
               compartment (pooled HR = 1.57; 95% CI = 1.04-2.37; P = 0.033) and a negative effect in the extra-tumoral
                                                                    [28]
               compartment (pooled HR = 0.76; 95% CI = 0.60-0.96; P = 0.022) .
               Stromal TIL-positivity was significantly associated with GC patient survival in multivariate analysis. High
                                                                                                       [29]
               densities of intratumoral-TIL has a tendency to be a favorable outcome indicator for GC patient survival .
               The prognostic impact of TILs has also been evaluated for GC patients with microsatellite instability-high
               (MSI-H). Higher densities of both intratumoral CD8+ and FOXP3+ TILs are significantly associated with
                            [30]
               longer survival . The prognostic impact of TILs has also been evaluated for patients with EBV-associated
               GC. EBV-associated GCs are more prevalent in CD8+ and FOXP3+ cell infiltration than EBV-negative GCs.
               CD8 expression and Foxp3 expression cell infiltration are associated with longer overall survival, whereas
                                                              [31]
               PD-L1 expression correlates with shorter overall survival .

               Most recent studies have focused on the significant association between PD-L1 expression and TILs. PD-L1
               expression is associated with high densities of TILs, mismatch repair deficiency and EBV positivity, but is not
                               [32]
               a prognostic factor . PD-L1 expression alone on tumor cells is not associated with survival of GC patients;
               however, patients with positive PD-L1 expression on a high density of TILs have a significantly shorter 5-year
               overall survival than those with negative PD-L1 expression. PD-L1 expression on TILs is an independent
                              [33]
               prognostic factor . It is associated with the corresponding immunoscore, which is quantified by the
               number of high-density areas of CD3+ and CD8+ TILs, both in the tumor regions and compartments of
                                 [34]
               MSI-H advanced GC . The levels of immunosuppressive protein expression PD-L1, cytotoxic T-lymphocyte
               antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO) in tumors and the densities of immune cells
               [CD3(+), CD4(+), CD8(+), or PD-1(+) cells] within the tumor microenvironment have been evaluated by
               immunohistochemical analysis. PD-L1 positive expression and a high-CD3 tumor microenvironment are
                                             [35]
               favorable prognostic markers in GC . Another study has also demonstrated that PD-L1 expression alone is
               not associated with overall survival; however, PD-L1-/CD8 high type is an independent indicator for longer
                                                                                                   [9]
               overall survival compared with PD-L1+/CD8 high. Adaptation of a recent molecular classification  based
               on EBV, MSI, E-cadherin and p53 showed no significant survival differences in this study. EBV+ and MSI-H
               GCs are associated with PD-L1+/CD8 high, and the PD-L1/CD8 status is associated with their prognostic
                                          [36]
               significance in stage II/III GCs . Recent studies have revealed that PD-L1 expression was significantly
               associated with GC patient prognosis only under the interaction between PD-L1 and TILs.


               TUMOR-ASSOCIATED MACROPHAGES
               TAMs play crucial roles in microenvironments. The polarization of macrophages into tumor-suppressive M1
                                                                                [37]
               or tumor-promoting M2 types is established in the microenvironment of GC . TAMs represent up to 50%
               of the tumor and are mainly M2 macrophages in invasive cancers. M2 macrophages support proliferation,
               invasion and metastasis by upregulating diverse growth factors, cytokines and extracellular matrix
               (ECM)-remodeling molecules, such as CCL2, CXCL12, CXCR4, TGFb, VEGF, PDGF, COX-2 and matrix
                                      [38]
               metalloproteinases (MMPs) . TAMs interact with T cells during tumor progression. M1 macrophages direct
               T cells towards Th1 tumoricidal responses. M1 macrophages are induced by NK cells that are produced by
               interferon-g (IFN-g) to amplify anti-tumor activity [39,40] . TAMs are identified by immunohistochemistry with
               the anti-CD68 antibody (pan-macrophage). Especially, M2 macrophages are identified with the anti-CD163
               antibody (M2 macrophage).

               A meta-analysis of 12 studies (n = 1388 patients) was conducted to evaluate the relationship between TAMs
               and GC prognosis. High total TAM infiltration levels in GC patients are associated with worse overall
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