Tumor-induced perturbations of cytokines and immune cell networks

Abstract

Until recently, the intrinsically high level of cross-talk between immune cells, the complexity of immune cell development, and the pleiotropic nature of cytokine signaling have hampered progress in understanding the mechanisms of immunosuppression by which tumor cells circumvent native and adaptive immune responses. One technology that has helped to shed light on this complex signaling network is the cytokine antibody array, which facilitates simultaneous screening of dozens to hundreds of secreted signal proteins in complex biological samples. The combined applications of traditional methods of molecular and cell biology with the high-content, high-throughput screening capabilities of cytokine antibody arrays and other multiplexed immunoassays have revealed a complex mechanism that involves multiple cytokine signals contributed not just by tumor cells but by stromal cells and a wide spectrum of immune cell types. This review will summarize the interactions among cancerous and immune cell types, as well as the key cytokine signals that are required for tumors to survive immunoediting in a dormant state or to grow and spread by escaping it. Additionally, it will present examples of how probing secreted cell-cell signal networks in the tumor microenvironment (TME) with cytokine screens have contributed to our current understanding of these processes and discuss the implications of this understanding to antitumor therapies.

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

“…CXCL10 has been shown to be produced by M1 cells. 7 Our data supported this report (Supplementary Figure 2); however, it remains to be further studied whether M1 cells actually secrete such functional chemokines. If this is the case, M1 cells could help convert prostate cancer from the prototypical cold tumor into a T cell inflamed tumor.…”

“…M1 macrophages have been reported to produce CXCL10. 7 In keeping with this, the expression levels of genes associated with M1 macrophages (CD68, CD80 and CD86) were significantly correlated with CXCL10 gene expression (Supplemental Figure 2).

10.1080/2162402X.2018.1486953-F0002Figure 2.Intratumoral chemokine expression after sipuleucel-T treatment (n = 14). (A) Differential expression of immune-related genes in high vs. low CD8 T cell infiltrated cases are shown.

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Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…These include elevated expression of the antiphagocytic signals CD200 and CD47 which have been associated with tumor progression and poor clinical outcome in several solid tumor types [81]. Secretion of immunosuppressive cytokines such as TGFβ, IL-10 and Fas-L within the tumor microenvironment can promote the expansion of Tregs and decrease the activation of cytotoxic T cells and NK cells [74]. Tumor cell secretion of indoleamine 2,3-dioxygenase (IDO) and galectins can impair antitumor T cell responses [74].…”

“…However, in the setting of cancer they are generally thought to be tumor promoting [73,74]. It has been shown that high percentages of CD25+FOXP3+ T cells infiltrate MCC tumors relative to normal skin (Figure 2: process 'F') [70].…”

“…Secretion of immunosuppressive cytokines such as TGFβ, IL-10 and Fas-L within the tumor microenvironment can promote the expansion of Tregs and decrease the activation of cytotoxic T cells and NK cells [74]. Tumor cell secretion of indoleamine 2,3-dioxygenase (IDO) and galectins can impair antitumor T cell responses [74]. Additionally, other cellular infiltrates, including myeloid derived suppressor cells, can promote tumor growth through numerous mechanisms including increased angiogenesis and disruption of antigen presentation [82].…”