Inflammatory Blood Monocytes Contribute to Tumor Development and Represent a Privileged Target To Improve Host Immunosurveillance

Abstract

Progressing tumors in humans and mice are frequently infiltrated by a highly heterogeneous population of inflammatory myeloid cells that contribute to tumor growth. Among these cells, inflammatory Gr-1+ monocytes display a high developmental plasticity in response to specific microenvironmental signals, leading to diverse immune functions. These observations raise the question of the immune mechanisms by which inflammatory monocytes may contribute to tumor development. In this study, we found that adoptive transfer of normal inflammatory Gr-1+ monocytes in tumor-bearing mice promotes tumor growth. In this tumoral environment, these monocytes can differentiate into tolerogenic dendritic cells (DCs) that produce IL-10 and potently induce regulatory T cell responses in vivo. Moreover, diverting the differentiation of Gr-1+ monocytes into tolerogenic DCs by forced expression of IL-10 soluble receptor and IL-3 in tumor cells improves host immunosurveillance by reducing the regulatory T cell frequency and by inducing immunogenic DCs in the tumor. As a consequence, tumor growth is strongly reduced. Our findings indicate that Gr-1+ monocytes represent a valuable target for innovative immunotherapeutic strategies against cancer.

Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum

“…In particular, immunosuppressive cells, including Tregs and MDSCs, are well known to play a central role in cancer-associated immunosuppression (4,5). In addition, inflammation in the cancer-bearing state promotes the emergence of these cells (6,7). Therefore, new therapeutic modalities to improve the immunosuppression and inflammation that accompany the cancer-bearing state are required.…”

“…in vivo was assayed as previously reported (15). Briefly, the abdominal wall of each mouse was opened under anesthesia and C26 cells (1x10 6 ), in a volume of 50 µl, were inoculated into the i.c., followed by closure of the abdominal wall. Mesenteric LNs were used as the tumor-draining LNs.…”

“…Although several explanations of their unsatisfactory performance could be proposed, the major reason that these therapies fail is believed to be due to the emergence of immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) (4,5). In addition, the tumor-bearing state is accompanied by chronic inflammation, and it is thought that the inflammatory state of cancer patients inhibits the efficacy of anticancer immunotherapy (6,7).…”

Mononuclear phagocyte heterogeneity in cancer: Different subsets and activation states reaching out at the tumor site

“…SOCS3, a STAT3-inducible protein, was shown to interact with pyruvate kinase type 2 (M2-PK) in TADC, resulting in decreased ATP production and DC dysfunction ). In the C26 colon adenocarcinoma model, CD11b + Gr-1 + inflammatory monocytes infiltrated the tumors and differentiated, under the influence of STAT3-activating IL-10, into MHC II low tolerogenic DC that produce IL-10 themselves and induce regulatory T-cell responses (Augier et al 2010). A very similar DC population is found in 3LL lung carcinoma tumors.…”

Bone marrow Th17 TNFα cells induce osteoclast differentiation, and link bone destruction to IBD

“…CD4 + T cells were isolated from the spleen, mesenteric lymph nodes (MLN) and BM as previously described,14 using the negative selection Kit CD4 + according to manufacturer's protocol (Life technologies, St Aubain, France).…”