Cytokines in immunogenic cell death: Applications for cancer immunotherapy.

Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis.

The interaction of LCK and the CD4 co-receptor alters the dose response of T-cells to interleukin-7.

CD8 and CD4 T-cells grow optimally under different concentrations of the cytokine, interleukin-7 (IL-7). While CD8 T-cells expand at high doses of IL-7, CD4 T-cells favor low doses. To examine the reason for the preference of CD4 T-cells for lower doses of the cytokine, we used IL-7 dependent T-cells to study signal transduction upon a range of IL-7 concentrations. We found that the high dose responsiveness of CD8 T-cells to IL-7 could be altered if these cells also expressed CD4. Using the phosphorylation of STAT5 as an indicator of growth, we found that the co-receptor associated kinase, LCK, contributed to phospho-STAT5 levels. Phospho-STAT5 was elevated at high dose IL-7 for CD8 T-cells and at low dose IL-7 for CD4 T-cells, which was reversed upon LCK inhibition. Examining the direct association of LCK with CD4 using a T- cell line that over-expresses CD4, we determined that CD4 could directly sequester LCK. Non-CD4 T-cells were not restricted in this manner and levels of phospho-STAT5 increased proportionally to the IL-7 dose. Our studies, therefore, show that the response of a T-cell to IL-7 can be modulated by the availability of LCK.

Ex vivo expansion of memory CD8 T cells from lymph nodes or spleen through in vitro culture with interleukin-7.

Interleukin-7 (IL-7) increases lymphocyte numbers, a critical feature of immune reconstitution, through mechanisms that are still poorly understood. Part of the problem is that IL-7 is produced in limited amounts by non-lymphoid cells, making in vivo studies of the cytokine's activity a challenge. To overcome this, we developed an in vitro system by which lymphocytes from secondary immune organs could be cultured to produce IL-7 responsive cells. Using this method, we showed that CD8(hi)CD44(hi) T cells accumulate in culture with IL-7 from a population of lymph node or splenic cells. These results were validated when a similar lymphocyte subset was found in mice expressing a constitutively active form of STAT5b, a key transducer of IL-7 signals. Interestingly, IL-7-expanded cells also up regulated the activation marker, CD69. The IL-7-derived CD44(hi)CD69(hi) cells were not generated from naïve cells, but expanded from an existing population, since culture in IL-7 of naïve lymphocytes from OT-1/Rag1(-/-) mice did not produce CD44(hi)CD69(hi) cells. Using the in vitro culture system to study lymphocytes from mice deficient in the apoptotic protein, BIM, we were able to attribute the expansion of CD8(hi)CD44(hi)CD69(hi) T cells to the proliferative and not survival activity of IL-7. The in vitro culture system provides an important new methodology to examine the activities of this essential as well as immunotherapeutic cytokine.

Interlinking interleukin-7.

The signaling processes that maintain the homeostatic proliferation of peripheral T-cells and result in their self-renewal largely remain to be elucidated. Much focus has been placed on the anti-apoptotic function of the cytokine, interleukin-7 (IL-7), during T-cell development. But a more critical role has been ascribed to IL-7 as a mediator of peripheral T-cell maintenance. The biological effects responsive to IL-7 signaling are transduced through only a few well-known pathways. In this review we will focus on the signals transduced by IL-7 and similar cytokines, examining how proliferative signals originate from cytokine receptors, are amplified and eventually alter gene expression. In this regard we will highlight the crosstalk between pathways that promote survival, drive cell cycle progression and most importantly provide the needed energy to sustain these critical cellular activities. Though this review showcases much of what has been learned about IL-7 proliferative signaling, it also reveals the significant gaps in our knowledge about cytokine signaling in the very relevant context of peripheral T-cell homeostasis.