Search

Glucocorticoids mediate potent anti-inflammatory and immunosuppressive effects. A chronic elevation of the endogenous glucocorticoid tonus subsequent to mental stress, as well as continuous treatment with exogenous glucocorticoids, activate an immunosuppressive transcription factor, TSC22D3, in dendritic cells, causing the subversion of cancer therapy-elicited antineoplastic immune responses and subsequent therapeutic failure.

Necrosis culminates in spilling cellular content through the permeabilized plasma membrane, thereby releasing potentially immunostimulatory molecules in the pericellular space of dead cells. Accordingly, molecules involved in necroptotic signaling, such as receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase-like (MLKL) have been found to stimulate anticancer immune responses in mouse models of chemotherapy. mRNAs encoding prominent pro-necrotic gene products (RIPK1, RIPK3, MLKL, PGAM5 and DFNA5) were correlated with immune-related metagenes in several cancer types (breast, colorectal, lung, ovary, melanoma), revealing the strongest associations in breast cancer. In two independent breast cancer cohorts, the expression of MLKL and DFNA5 was decreased at the mRNA levels in tumor as compared with normal tissues. Moreover, MLKL expression exhibited a strong positive correlation with genes reflecting the presence of B, NK and T lymphocytes in the tumor bed, in multiple distinct breast cancer subtypes. In contrast, the positive correlation between RIPK3 and lymphoid cells was restricted to HER2+ and triple negative/basal-like breast cancer. Moreover, the expression of DFNA5, which mediates post-apoptotic secondary necrosis, mostly correlated with the monocytic lineage and macrophages in ER+/luminal A breast cancers. MLKL (and to some extent RIPK1 and RIPK3) was strongly associated with the local expression of genes involved in interferon-α and interferon-γ responses. Altogether, these results support the idea that pro-necrotic signaling facilitates intratumoral immune responses in human breast cancer.

The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor α (TNFα). However, blocking the TNFα/TNF receptor (TNFR) system by three different strategies—namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout—failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNFα-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA 205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFα is not required for anthracyclines to elicit therapeutic anticancer immune responses. [ABSTRACT FROM AUTHOR]

Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that-at least in some clinical settings- the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies. [ABSTRACT FROM AUTHOR]

Tumor cells succumb to chemotherapy while releasing ATP. We have found that extracellular ATP attracts dendritic cell (DC) precursors into the tumor bed, facilitates their permanence in the proximity of dying cells and promotes their differentiation into mature DCs endowed with the capacity of presenting tumor-associated antigens. [ABSTRACT FROM AUTHOR]

Retrospective clinical data indicate that cardiac glycosides (CGs), notably digoxin, prolong the survival of carcinoma patients treated with conventional chemotherapy. CGs are known to influence the immune response at multiple levels. In addition, recent results suggest that CGs trigger the immunogenic demise of cancer cells, an effect that most likely contributes to their clinical anticancer activity. [ABSTRACT FROM AUTHOR]