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Introduction To explore the relationship between the tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs), and their distribution characteristics as well as the prognostic value in gastric cancer (GC). Material and methods The TLSs and four subtypes of TILs were assessed by immunohistochemical (IHC) staining. The presence of MECA-79 positive high endothelial venules (HEVs) identified among the ectopic lymphocyte aggregation area in the GC tissue was defined as valid TLSs. The number of labeled TILs was observed in 5 fields of the most positive cells in the tumor center, invasive edge and within the TLSs, at a field of vision ×40. Results The TLS distribution was significantly higher in the tumor invasive edge than the tumor center (p < 0.001). Similarly, the infiltrating density of CD8+ T cells and GrB+ T cells was statistically significantly higher in the tumor infiltrating edge than the tumor center. The total number of TILs and FOXP3+ T cells showed a contrary distribution. There was a positive correlation of the density of TLSs and TILs with both the location and the immune phenotype. A higher frequency of TILs and TLSs is often associated with favorable clinicopathologic parameters. Higher numbers of peri-TLSs (p = 0.007), peri-CD8+ (p = 0.019) and peri-GrB+TILs (p = 0.032) were significantly correlated with the favorable overall survival. Multivariate analysis revealed that the densities of TILs (p = 0.019) and TLSs (p = 0.037) were independent prognostic predictor for GC patients. Conclusions We provide evidence that TLSs were positively associated with lymphocyte infiltration in GC. Thus, the formation of TLSs predicts advantageous immune system function and can be considered as a novel biomarker to stratify the overall survival risk of untreated GC patients.

Tumor infiltration pattern (INF) and tumor origin site were reported to significantly affect the prognosis of gastric cancer (GC), while the immune status under these contexts is not clear. In this study, we correlated the density and phenotype of tumor-infiltrating lymphocytes (TILs) with INF and the tumor origin site to reflect the biological behavior of tumors from a new perspective and also determined their effects on overall survival (OS) and other related clinicopathological features in archival samples of 147 gastric cancers with 10-year follow-up data. We found that the INFc growth pattern (an invasive growth without a distinct border) of GC lacked immune cell infiltration, particularly the cytotoxic T cells and their activated form. It is also significantly associated with an unfavorable prognosis (P < 0.001) and proximal site (P = 0.001), positive lymph node metastasis (P = 0.002), and later tumor–node–metastasis stage (P < 0.001). Moreover, the density and sub-type of TILs infiltration were significantly different in disparate differentiated areas for the tumor tissue with INFb. Compared with distal gastric cancer, proximal gastric cancers were prone to grow in an INFc pattern (P = 0.001) and infiltrated with fewer TILs, experiencing a shorter survival time (P = 0.013). Multivariate analysis showed that only the INF and the density of TILs were demonstrated to be the independent prognostic factors of OS for the GC. We concluded that GC with an aggressive growth pattern arising from proximal sites always had a weak immune response and resulted in a poor prognosis. The interaction between them and their synergistic or antagonistic effects in the development of tumors need to be further studied. This study opens up a new perspective for research on the biological behavior of the tumor.

Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining. Molecular analysis revealed an EGFR exon 19 deletion and with an excellent response to Gefitinib treatment. Microscopic examination of recurred tumor specimens revealed a diffuse poorer differentiated proliferation of atypical cells. Immunostaining showed intensive Vimentin but almost completely negative for E-cadherin and TTF-1. Genetic analyses revealed T790M mutation. It is worth noting that rare clinical studies have been reported that acquired EGFR-TKI resistant lung adenocarcinoma underwent T790M mutation and almost complete EMT together. More significantly, the similarity of poorly differentiated cancer cell cluster in the primary lesions to recurred tumor lesions, which may pre-harbor drug resistance mutation should not be neglected underneath the predominant morphologic patterns.

Local radiotherapy is the major therapeutic approach to control inoperable cervical cancer. In this study, we analyzed the local immune microenvironment of cervical cancer before and after clinical radiation therapy to investigate whether tumor response due to immunomodulation. A total of 59 patients with pathologically diagnosed cervical cancers classified according to the International Federation of Obstetrics and Gynecology (FIGO) criteria were recruited. The patients were treated according to their disease status with standard radiation regimens. For each patient, tumor biopsies were conducted before, during and after radiation treatment with the doses of 0, 10, 20 and 30 Gy, respectively. All of the tumor samples were then grouped according to the doses delivered and tumor infiltrating lymphocytes with the biomarkers of CD8, CD4, FOXP3 and OX40 were measured by in situ immunohistochemistry. We found that before radiation treatment both CD8(+) T cell and CD4(+) T cell infiltrates were more present in the tumor stroma than in the tumor nests, while OX40(+) and FOXP3(+) T cell infiltrates were present at similar levels in both the tumor nests and stroma. After radiation treatment, the levels of CD8(+) T cells and CD4(+) T cells in the tumor nests and stroma were decreased compared with the levels before irradiation. However, OX40(+) T cells and FOXP3(+) T cells did not show any difference before and after irradiation, which indicates that the FOXP3(+) T cells were more resistant to ionizing radiation than were the cytotoxic effector T cells and demonstrates a dynamic rebalance of infiltrating lymphocytes in the tumor milieu occurs after radiotherapy. This suggest that local antitumor immunity could be compromised due to decreased cytotoxic effector cells and the relatively stable status of FOXP3(+) T cells after irradiation. Therefore, regulation of these FOXP3(+) T cells may be a potentially effective approach to enhance the efficacy of cancer radiation therapy.