Survival of effector CD8+ T cells during influenza infection is dependent on autophagy.

The activation and expansion of effector CD8(+) T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5(-/-) CD8(+) T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5(-/-) effector CD8(+) T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8(+) T cells require autophagy to suppress cell death and maintain survival in response to a viral infection.

Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Ganglioside GD2 has been previously found on the cell surface in various tumor types, including osteosarcomas. FINDINGS: In this study, forty-nine additional osteosarcoma samples from 14 individual patients were assessed for GD2 expression via immunohistochemistry, of which 47 samples were found to express GD2. In matched samples from patients, GD2 expression seen at initial biopsy was found to persist in 100% of tissues taken at recurrence. CONCLUSIONS: GD2 expression was found to persist upon recurrence. These results suggest a phase 2 trial in children with recurrent osteosarcoma should provide an appropriate read out on the efficacy of anti-GD2 antibody.

Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity.

Tumors and the immune system are intertwined in a competition where tilting the fine balance between tumor-specific immunity and tolerance can ultimately decide the fate of the host. Defensive and suppressive immunological responses to cancer are exquisitely sensitive to metabolic features of rapidly growing tumors, such as hypoxia, low nutrient availability, and aberrant growth factor signaling. As a result, clinical therapies impacting these properties change the in situ antitumor immune response by virtue of disrupting the tumor environment. To compensate for disruptions in cellular metabolism, cells activate autophagy to promote survival. On the basis of this notion, strategies designed to block autophagy in tumor cells are currently being tested in several human clinical trials. However, therapies that impair tumor metabolism must also take into account their effect on lymphocytes activated in the immune response to cancer. Given that a strong antitumor immune response is a positive prognostic factor in overall patient survival, identifying ways to block essential processes in tumor cells and suppressive immune cells while promoting those that are important for a robust immune response are of critical importance. Herein, we review the effects of anti-cancer agents that impact metabolism administered concurrently with autophagy inhibitors on immune cells and consider the implications for patient response to therapy.

Implications of therapy-induced selective autophagy on tumor metabolism and survival.

Accumulating evidence indicates that therapies designed to trigger apoptosis in tumor cells cause mitochondrial depolarization, nuclear damage, and the accumulation of misfolded protein aggregates, resulting in the activation of selective forms of autophagy. These selective forms of autophagy, including mitophagy, nucleophagy, and ubiquitin-mediated autophagy, counteract apoptotic signals by removing damaged cellular structures and by reprogramming cellular energy metabolism to cope with therapeutic stress. As a result, the efficacies of numerous current cancer therapies may be improved by combining them with adjuvant treatments that exploit or disrupt key metabolic processes induced by selective forms of autophagy. Targeting these metabolic irregularities represents a promising approach to improve clinical responsiveness to cancer treatments given the inherently elevated metabolic demands of many tumor types. To what extent anticancer treatments promote selective forms of autophagy and the degree to which they influence metabolism are currently under intense scrutiny. Understanding how the activation of selective forms of autophagy influences cellular metabolism and survival provides an opportunity to target metabolic irregularities induced by these pathways as a means of augmenting current approaches for treating cancer.