Occurrence of Tertiary Lymphoid Tissue Is Associated with T-Cell Infiltration and Predicts Better Prognosis in Early-Stage Colorectal Cancers

Abstract

Purpose: Tumor-infiltrating T lymphocytes (TIL) play a key role in the clinical outcome of human colorectal cancer; however, the dynamics of their recruitment along colorectal cancer clinical progression have not been fully elucidated. Tertiary lymphoid tissue (TLT) is an ectopic organized lymph node-like structure that typically forms at sites of chronic inflammation and is involved in adaptive immune responses. Its occurrence in cancer is sporadically documented and its role and clinical relevance is largely unknown.Experimental Design: The occurrence of TLT, the correlation with TILs, and the clinical relevance were evaluated retrospectively, in a cohort study involving a consecutive series of 351 patients with stage II and III colorectal cancer. The role of TLT in lymphocyte recruitment was assessed in a preclinical model of colorectal cancer.Results: In both human colorectal cancer and in a murine model of colorectal cancer, we identified organized TLT, highly vascularized (including high endothelial venules), and correlated with the density of CD3 þ TILs. Intravenous injection in mice of GFP splenocytes resulted in homing of lymphocytes to TLT, suggesting an active role of TLT in the recruitment of lymphocytes to tumor areas. Accordingly, TLT density and TIL infiltration correlated and were coordinated in predicting better patient's outcome among patients with stage II colorectal cancer. Conclusions:We provide evidence that TLT is associated with lymphocyte infiltration in colorectal cancer, providing a pathway of recruitment for TILs. TLT cooperates with TILs in a coordinated antitumor immune response, when identifying patients with low-risk early-stage colorectal cancer, thus, representing a novel prognostic biomarker for colorectal cancer.

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

“…In particular, the IL-23/IL-17 axis has been linked to worse outcome in CRC patients 32 and has been recognized to drive colorectal carcinogenesis in experimental models, 33 through a variety of mechanisms that include a direct promotion of enterocyte proliferation by IL-17. 34 Conversely, CD8 C T cell infiltration has been recognized as a major prognostic factor in CRC prognosis, 10 an event probably favored by follicular helper response and tertiary lymphoid structure formation, 11,35 indicating the attempts of protective immune-surveillance to counteract tumor progression.…”

“…[7][8][9] Besides CD8 C T cell infiltration, 10 the occurrence of ectopic lymphoid tissue, often localized at the invasive cancer front, has a favorable prognostic impact for early stage CRC. 11 Specialized Treg subsets, such as T follicular regulatory cells (Tfr), are devoted to antagonize follicular responses. 12 The goal of our study was to characterize at several levels (phenotypical, functional and epigenetic) the Tregs infiltrating human CRC specimens, in order to assess whether they exerted suppressive function ex vivo, presented a Helios high , OX40…”

Causes of Variation in The Neutrophil–Lymphocyte and Platelet–Lymphocyte Ratios: a Twin-Family Study

“…A higher NLR indicates a shift in the balance between neutrophil and lymphocytes, which in our sample was due to both a decrease in lymphocyte count and an increase in neutrophil count. Lower lymphocyte counts are associated with poorer survival in different types of cancer [43,44], while high lymphocyte counts are related to better responses to cytotoxic treatment and to better prognosis in cancer patients [45]. Neutrophils have also been reported to secrete tumor growth promoting factors, including vascular endothelial growth factor, For the purpose of the overview, BMI was classified in four categories: underweight (BMI <18.5), normal (18.5-24.9), overweight (25.0-29.9) and obese (BMI ≥30).…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…Tertiary lymphoid structures (TLSs; also called ectopic lymphoid structures, ELSs) are inducible lymphoid aggregates that phenotypically and functionally resemble secondary lymphoid organs 4. TLSs can develop in tissues where persistent inflammation is present, and a correlation between high TLS densities and prolonged patient survival has been reported for several cancers including breast,5, 6 lung,7, 8 melanoma,9 pancreatic10 and colorectal 11, 12. TLS gene signatures, that include homeostatic chemokines such as CXCL13 , CCL19 and CCL21 , have the potential to represent prognostic indicators of cancer progression in melanoma13 and colorectal cancer 14, 15.…”

“…Improved patient survival in non‐small‐cell lung carcinoma has also been linked with TLSs, where follicular B cells and plasma cells show antibody specificity to tumour antigens 8. However, TLS involvement and activity may only have prognostic value in certain stages of tumour development or for certain types of cancer 11, 18, 19. Thus, greater mechanistic insights are required to establish the link between TLS formation, tumour progression and clinical outcome.…”