Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Abstract

Infiltration of CD8 + T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including Triple Negative Breast Cancers (TNBC). However, the mechanisms underlying different infiltration-levels are largely unknown. Here, we have characterized the spatial profile of CD8 + T cells around tumor-cell clusters in the core and margin regions in TNBC. Combining mathematical modeling and data analysis, we propose that there exists a possible chemo-repellent inside tumor-cell clusters, which prevents CD8 + T cells from infiltrating into tumor-cell clusters. Furthermore, investigation into the properties of collagen fibers suggests that variations in desmoplastic elements does not limit infiltration of CD8 + T lymphocytes into tumor-cell clusters. This is consistent with the prediction of our mathematical modeling analysis whereby CD8 + T cells are predicted to infiltrate the fibrotic barrier and their infiltration into tumor clusters is governed by other mechanisms involving a local repellent.tumor-infiltrating lymphocytes | tumor-cell clusters | extra-cellular matrix | triple-negative breast cancer X.L.

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

“…Collagen fiber orientation was described as the coefficient of variation (CV) of the angle for all fibers, the smaller the CV is, the more aligned the fibers are. Fibers in non-treated tumors remained mainly oriented in one dominant direction (Figures 3B, 3C and 3F) with a CV from 1.85 to 0.5 consistent with previous findings (35). LOX inhibition tends to disrupt the alignment of collagen fibers, meaning that they were more dispersed and oriented in different directions with increased CV as compared to control conditions.…”

“…Likewise, in aged skin, dermal fibroblasts harbor a phenotype similar to CAFs and produce ECM matrices that limit T cell displacements (43). However, in triple-negative breast cancers and in pancreatic tumors T cells were still found in dense networks of collagen fibers (35,44). Since most of the aforementioned studies were correlative, we decided in this study to specifically alter the ECM network by LOX inhibition and investigated the consequences on T cell motile behavior.…”

Fractal dimension, occupancy and hotspot analyses of B cell spatial distribution predict clinical outcome in breast cancer

“…However, it is well known that the higher the density of TILs and leukocytes infiltrating into cancer cell islands, the better the prognosis. The "inflamed" tumors were associated with a better response to immunotherapy than the "noninflamed" and "immune-excluded" tumors (12,(30)(31)(32)(33). Similarly, we find that higher densities of B cells as well as CD8 + and CD3 + T cells (and Th cells and Tregs to a lesser extent) in the cancer cell islands are also correlated with improved prognosis (Fig.…”

“…This indicates that differences in physical topography may not be the explanation. It may be that CD20 + B cells, CD8 + T cells and CD3 + T cells in good outcome patients are more responsive to chemokines secreted by tumor cells and are more successful in finding their cognate antigens within the tumor microenvironment as in a recently published study (36).…”

<p>Transcriptional Characterization Of The Tumor Immune Microenvironment And Its Prognostic Value For Locally Advanced Lung Adenocarcinoma In A Chinese Population</p>

“…29 Therefore, it is crucial to measure the extent of CD8+ T cell infiltration of solid tumors. 30 Our GSVA analysis also demonstrated that enrichment of the antigen processing pathway (P = 0.01), and possibly the lymphocyte activation pathway (P = 0.08), correlated with better prognosis ( Figure S1). The antigen processing pathway prepares antigens by converting them into MHC-I bound peptides for presentation to T lymphocytes.…”