Suppression of canine myeloid cells by soluble factors from cultured canine tumor cells

Abstract

Background Cancer profoundly affects immunity and causes immunosuppression that contributes to tumor escape, metastases and resistance to therapy. The mechanisms by which cancer cells influence immune cells are not fully known but both innate and adaptive immune cells can be altered by cancer. Myeloid cells are innate immune cells that comprise the mononuclear phagocytic system (MPS) and include monocytes, macrophages, dendritic cells (DCs) and their progenitors. Myeloid cells play important roles in both the promotion and regulation of immune responses. Dysregulated myeloid cells are increasingly being recognized as contributing to cancer-related immunosuppression. This study investigated whether soluble factors produced by canine tumor cells inhibited canine myeloid cell function. Methods These studies investigated the utility of using the canine DH82 cell line for assessment of canine myeloid responses to tumor-derived soluble factors (TDSFs). Phenotypic comparisons to canine bone marrow-derived DCs (BM-DCs) and bone marrow-derived macrophages (BM-MΦs) were performed and expression of myeloid cell markers CD11b, CD11c, CD80, and major histocompatibility complex (MHC) class II were evaluated by flow cytometry. Phenotypic and functional changes of DC populations were then determined following exposure to tumor-conditioned media (TCM) from canine osteosarcoma, melanoma and mammary carcinoma cell lines. Results We found that the canine BM-DCs and the DH82 cell line shared similar CD11b, CD11c and MHC II expression and morphologic characteristics that were distinct from canine BM-MΦs. Myeloid cells exposed to TDSFs showed decreased expression of MHC class II and CD80, had reduced phagocytic activity and suppressed the proliferation of responder immune cells. Conclusion These results show that soluble factors secreted from canine tumor cells suppress the activation and function of canine myeloid cells. Our results suggest that, similar to humans, dysregulated myeloid cells may contribute to immunosuppression in dogs with cancer.

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

“…There are few reports describing the effect of OSA on monocyte surface receptor expression in dogs. For example, down‐regulation of MHC class II and CD80 in canine myeloid cells when exposed to tumor cell lines including OSA in vitro has been observed . In humans, the prevalence of an immunosuppressive phenotype in peripheral blood monocytes of OSA patients has been observed .…”

“…For example, down-regulation of MHC class II and CD80 in canine myeloid cells when exposed to tumor cell lines including OSA in vitro has been observed. 24 In humans, the prevalence of an immunosuppressive phenotype in peripheral blood monocytes of OSA patients has been observed. 13 However, to the authors' knowledge, there are no reports evaluating phenotypic changes in monocytes of clinical dogs with OSA.…”

CSPG4-Specific Immunity and Survival Prolongation in Dogs with Oral Malignant Melanoma Immunized with Human CSPG4 DNA

“…However, it is possible that other T-cell parameters, such as vaccine-elicited T-cell phenotype, the ability to release other cytokines and the presence of cells negatively regulating the immune response, may have an impact. The immunosuppressive microenvironment at the tumor site and draining LN (48,49) may have locally inhibited the vaccine-induced immune response, allowing local recurrences and/or metastasis to other satellite LN to occur in some dogs.…”

Canine mammary cancer cells direct macrophages toward an intermediate activation state between M1/M2

“…Our data corroborates previous studies. Wasserman et al (2012) demonstrated the capacity of several canine cancer cells to inhibit macrophage MHC II expression, therefore driving TAMs into the alternative M2-activation pathway [ 32 ]. Król et al (2012) [ 16 ] showed that LPS-induced activation of macrophages was inhibited by co-culturing macrophages with canine mammary cancer cells.…”

“…For example, an intermediary form of macrophages has recently been identified as regulatory macrophages, presenting elevated IL-10 and low IL-12 secretion [ 4 ]. During the M1-to-M2 transition of macrophages the molecular changes occurring can have profound effect on breast cancer cell behaviour; notably, the levels of the cytokines CSF-1 and CCL2 are elevated during this transition [ 16 , 32 ]. CSF-1 and CCL2 are known modulators of the fate of macrophages, both driving the production of M2 cells and being correlated to poor prognosis in cancer [ 5 , 28 ].…”