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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