An increasing body of evidence supports a contribute of the immune system in cancer development and progression, in fact recent data have demonstrated that, virtually, every tumor has an inflammatory cell infiltrate as part of a complex tumor microenvironment (TME). Cancer progression is also directed by the involvement of organs located at distant sites from the primary tumor due to the release of tumor-derived soluble factors (TDSFs). Therefore, it is very important to consider not only the role of the tumor-associated stroma, which is known as TME, but also the creation of a network even with distal compartments due to the release of many TDSFs leading to the generation of the so-called tumor macroenvironment. Recently, the macroenvironment changes have been underlined in the genetic model of colon cancer ApcMin/+, where a significantly higher total IgA levels in ApcMin/+ tumor-bearing mice has been demonstrated. In this work, the possible mechanisms of the IgA skewing have been dissected in the colorectal cancer (CRC) context. The data demonstrated that the sole IgA skewing is not a tract present in all CRC models, but that it is peculiar of the ApcMin/+ mice; the presence of the IgA sewing in mouse tumor models not associated with the intestinal tract was also excluded. Considering the association of several intestinal diseases with increased intestinal permeability, the damaged intestinal barrier, which can lead to the translocation of bacteria, was proposed to be associated with the tumor progression. A higher presence of bacterial level in the ApcMin/+ compared to the WT mice was detected, indicating an increased microbial translocation to the liver. Furthermore, the presence of Bacteroides fragilis in the ApcMin/+ mice was found, a type of bacteria that was instead absent in the WT counterpart. Our data indicate the carcinogenic potential of the microbiota in the ApcMin/+ tumor context, since it has been demonstrated a tumorigenic role for B. fragilis. The data, herein presented, suggest a direct or indirect association of the microbiota in the ApcMin/+ tumor setting compared to the healthy mice. The progresses in the study of the immune microenvironment have mainly highlighted the role of immunosuppressive T cell in the inhibition of the antitumor immune response. Instead, the role of B cells is less well understood. In the present work, the presence of a accumulation of MDSCs in the CRC TME and the ability of splenic MDSCs from MC38 tumor-bearing mice to affect the phenotype of B cells, inducing a shift towards an immunosuppressive B cell phenotype, have been highlighted. In particular, the ability of splenic MDSCs isolated from MC38 tumor-bearing mice was reported to induce the expansion of the IL-10 competent B cells and to increase the expression of FasL, PD-L1, and IgA on naïve B cells. This work might be, therefore, helpful for clarifying the alteration of the systemic tumor environment occurring in CRC and for the development of new potential immunotherapeutic strategies.
|Titolo:||INFLUENCE OF MICRO- AND MACROENVIRONMENT IN COLON CANCER|
PACE, GIADA (Corresponding)
|Data di pubblicazione:||2019|
|Appare nelle tipologie:||07.13 Doctoral Thesis|