Willard-Gallo, K. | Search bioRxiv

bioRxiv2024

Favorable histo-molecular remodeling of pancreatic ductal adenocarcinoma after Total Neoadjuvant Therapy including Stereotactic Body Radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest tumors with slow progress in systemic therapies due to its peculiar and resistant tumor microenvironment. Inclusion of isotoxic high-dose stereotactic body radiation therapy (iHD-SBRT) into a total neoadjuvant strategy (TNT) is promising for the treatment of localized PDAC. However, the histo-molecular effects of iHD-SBRT are still poorly explored. In this study, we have shown that TNT, associating FOLFIRINOX [FFX] followed by iHD-SBRT, leads to significant and long-lasting remodeling of PDAC, affecting its stromal, metabolic, and molecular features. Contrary to FFX alone, TNT is able to enrich tumors with Classical and Inactive stromal signatures associated with better prognosis. Furthermore, iHD-SBRT seems capable to counteract several of the detrimental modulatory effects induced by FFX such as Epithelial-to-Mesenchymal Transition or angiogenesis. Additionally, we identified inflammatory cancer-associated fibroblasts signatures as an important prognostic factor. This work provides new rationale to sequentially combine FFX with iHD-SBRT and suggests new pathways that can be targeted in combination with a TNT. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/591890v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@155da78org.highwire.dtl.DTLVardef@17a1ab7org.highwire.dtl.DTLVardef@16fe522org.highwire.dtl.DTLVardef@12c5870_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Characterization of immunoactive and immunotolerant CD4+ T cells in breast cancer by measuring activity of signaling pathways that determine immune cell function

Cancer immunotolerance can be reversed by checkpoint blockade immunotherapy in some patients, but response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses against cancer. Conversion to an immune suppressive state impairs the anti-cancer immune response and is mainly effected by CD4+ Treg cells. A number of signal transduction pathways activate and control functions of CD4+ T cell subsets. As previously described, assays have been developed which enable quantitative measurement of the activity of signal transduction pathways (e.g. TGF{beta}, NF{kappa}B, PI3K-FOXO, JAK-STAT1/2, JAK-STAT3, Notch) in a cell or tissue sample. Using these assays, pathway activity profiles for various CD4+ T cell subsets were defined and cellular mechanisms underlying breast cancer-induced immunotolerance investigated in vitro. Results were used to measure the immune response state in a clinical breast cancer study. MethodsSignal transduction pathway activity scores were measured on Affymetrix expression microarray data of resting and immune-activated CD4+ T cells, immune-activated CD4+ T cells incubated with breast cancer tissue supernatants, CD4+ Th1, Th2, and Treg cells, and of clinical study samples in which CD4+ T cells were derived from blood, lymph node and cancer tissue from primary breast cancer patients (n=10). ResultsIn vitro CD4+ T cell activation induced PI3K, NF{kappa}B, JAK-STAT1/2, and JAK-STAT3 pathway activity. Simultaneous incubation with primary cancer supernatant reduced PI3K and NF{kappa}B, and partly reduced JAK-STAT3, pathway activity, while simultaneously increasing TGF{beta} pathway activity; characteristic of an immune tolerant state. CD4+ Th1, Th2, and Treg cells all had a specific pathway activity profile, with activated immune suppressive Treg cells characterized by high NF{kappa}B, JAK-STAT3, TGF{beta}, and Notch pathway activity scores. An immune tolerant pathway profile was identified in CD4+ T cells from tumor infiltrate of a subset of primary breast cancer patients which could be contributed to activated Treg cells. A Treg pathway profile was also identified in blood samples. ConclusionSignaling pathway assays can be used to quantitatively measure the functional immune response state of lymphocyte subsets in vitro and in vivo. Clinical results suggest that in primary breast cancer the adaptive immune response of CD4+ T cells has frequently been replaced by immunosuppressive Treg cells, potentially causing resistance to checkpoint inhibition. In vitro study results suggest that this effect is mediated by soluble factors from cancer tissue (e.g. TGF{beta}). Signaling pathway activity analysis on TIL and/or blood samples is expected to improve predicting and monitoring response to checkpoint inhibitor immunotherapy.

cancer biology↗