TILs in Invasive Tumor Margins May Hold a Key to Gastric Cancer Prognosis

An analysis presented at 2022 IGCC showed that the level of CD8 + cells in the outer margin of gastric cancer tumors was significantly associated with survival outcomes and could inform prognosis.

An analysis of gastric cancer indicated that invasive tumor margins harbor essential genomic information that may inform overall disease prognosis, but sampling using tissue microarrays (TMA) may be missing important genomic information.1

“Tumor infiltrating lymphocytes, or TILs, play an important role in anticancer immunity since they are directed at cancer cells. In many cancer types, TILs are a prognostic marker,” Tanya Soeratram, a PhD student at Amsterdam University Medical Centers, said in a presentation of the data at the 2022 International Gastric Cancer Congress.

Relating to the presence of TILs, tumors can be characterized as either “hot” or “cold” based on the levels of high or low infiltration, respectively. TILs may also accumulate to a specific location in the tumor. Those with TILs isolated to the invasive front, which makes up the area around the tumor center, may also have a poor prognosis like cold tumors, according to Soeratram.

In gastric cancer, however, different results have indicated that TILs may not be an as important a prognostic marker as in other tumor types. This could be explained by differences in therapy, regions analyzed which do not always including the invasive margin, cut-off strategies, and analysis methods.

“The aim of this study was to find the best combination of immune biomarkers that stratify patients with different survival outcomes,” Soeratram said.


Patients considered for the current analysis (n = 71) had resectable gastric cancer and were treated as part of the D1D2 study, in which standardized extended lymphadenectomy (D2) did not improve survival and was associated with a higher rate of adverse events mortality vs standardized limited lymphadenectomy (D1).2 In total, 251 tissue blocks were evaluated by immunohistochemistry (IHC) for the 5 most-studied markers: CD3, CD45RO, CD8+ pan-cytokeratin, FOXP3, and Granzyme B.

Samples were scanned digitally by QuPath and manual tumor annotation was performed by which the tumor border was expended. Using a grid system, positive cell detection was automated, and cell density was analyzed for each tile in the grid.

A classification and regression tree (CART) analysis was used to select the most prognostic markers and determine a cut-off that divides patients into groups of maximum survival differences. The prognostic markers that were identified as significant were CD8+ cells in the outer margin (OM; cut-off 798 cells/mm3) and FOXP3 in the tumor center (TC; cut-off 20 cells/mm3). Three patient subgroups were then defined as:

  1. Those with high (≥798 cells/mm3) CD8+ cells in the OM (CD8 OM-Hi; n = 36)
  2. Those with low (<798 cells/mm3) CD8+ cells in the OM and high (≥20 cells/mm3) FOXP3 in the TC (CD8 OM-Low/FOXP3 TC-Hi; n = 103)
  3. Those with low CD8+ cells in the OM and low (<20 cells/mm3) FOXP3 in the TC (CD8 OM-Low/FOXP3 TC-Low; n = 99)


Charting the cancer-specific survival for the 3 subgroups, the CD8 OM-Hi group had the strongest survival probability, followed by CD8 OM-Low/FOXP3 TC-Hi, then CD8 OM-Low/FOXP3 TC-Low (log-rank P <.0001).

“When we look at the molecular subgroups, we found that the CD8 OM-high group was enriched with [Epstein-Barr virus–positive tumors], Lauren intestinal subtype, lower T stage, and lower N stage compared with the other subgroups,” Soeratram said. “When then performed a multivariate cox proportion analysis to determine the CART groups were predictive markers of prognosis.”

The investigators concluded that the 3 prognostic groups were indeed predictive of outcomes. Using CD8 OM-Hi group as the reference group, the hazard ratios for survival were 5.02 (95% CI, 2.03-12.42; P <.0001) and 7.99 (95% CI, 3.22-19.86; P <.0001) for the CD8 OM-Low/FOXP3 TC-Hi and the CD8 OM-Low/FOXP3 TC-Low groups, respectively. Other factors that were independent predictors of prognosis were stage pT3/4 (HR, 3.46; 95% CI, 2.04-5.86; P <.0001), stage pN1-3 (HR, 2.10; 95% CI, 1.33-3.31; P <.001) and D2 surgery (HR, 0.67; 95% CI, 0.48-0.95; P = .025)

“The invasive margin in gastric cancer holds essential information and this could be missed by TMA sampling and will be missed when using biopsies,” Soeratram concluded.


  1. Soeratram T. Association of tumor infiltrating T-lymphocytes with survival in resectable gastric cancer. Presented at: 2022 International Gastric Cancer Congress; March 6-9, 2022; Houston, TX.
  2. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010;11(5):439-449. doi:10.1016/S1470-2045(10)70070-X
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