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TOX: a rediscovered master molecular actor to enhance immuno-oncology interventions

Cellular & Molecular Immunology volume 17, pages 558–560 (2020)Cite this article

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The cellular immune response to cancer is the result of a complex and partially redundant network of immunoregulatory interactions implemented by three main cell types: antigen-presenting cells (APCs), T cells, and tumor cells. The control of cell fates—notably, those of T cells—exerted by transcriptional regulators in response to extracellular signal sensing and transduction is critical to the adaptive immune system. The release of prosurvival and proinflammatory cytokines such as IL-2 and IFN-γ promotes a cytotoxic CD8+ T-cell response in which debris released from apoptotic tumor cells is subsequently taken up by APCs and presented in a cycle of immunogenic cell death, a process to which the efficacy of conventional chemotherapies can be at least partially ascribed.7 The mechanism of action of checkpoint inhibitors is to counteract the upregulation of immunoinhibitory molecules (e.g., CTLA-4 or PD-1) or their ligands (e.g., B7-1 and B7-2 or PD-L1 and PD-L2, respectively), which is adaptively promoted by tumor cells after prolonged immune activation, ultimately driving escape from immune attack. Although the network of cytokines in clinical cancer has been described in some detail, notably highlighting the critical roles of the immunostimulatory molecules IL-2, IL-12, IL-15, IL-21, and GM-CSF as well as IFN-α, and those of the immunosuppressive cytokines TNF-α, TNF-β, CSF-1, CXCL8/IL-8, VEGF, and CCR2/CCR5,8 much is unknown.

Another prism of analysis in cancer relates to the prominent intratumor dynamics that characterize neoplastic lesions, perhaps best exemplified by the tremendous diversity observed in advanced melanoma. From the initiation of the neoplastic process to the development of metastases, cancer can be considered through the lens of both population dynamics and single-cell oncogenic mutations. Global transcriptomic and proteomic analyses have enabled the discovery of main nodes in the chronic inflammation/cancer response network. Moreover, these analyses have been useful in highlighting a potential critical role of the transcriptional regulator TOX (thymocyte selection associated high-mobility group box) in CD8+ T-cell differentiation and dysfunction.9 However, what has remained insufficiently clarified is the identity of the precise mechanisms that underlie T-cell differentiation and divergence, including the emergence of resident memory T cells,10 during active and chronic infection, notably characterized by a change in the microenvironment to which T cells need to adapt. During acute infection, naive CD8+ T cells proliferate, expand clonally, and differentiate into effector CD8+ T cells, which control infection via direct killing.11 During chronic infection and in cancer, T-cell populations typically become exhausted due to chronic antigen stimulation; that is, their effector functions become attenuated, with decreased cytokine production, whereas their inhibitory receptors, including PD-1, LAG-3, TIGIT, CD38, CD39, CD160, 2B4, TIM-3, and CTLA-4, are upregulated.12 Terminally exhausted T cells thus exhibit a reduced capacity to destroy malignant cells, a phenomenon to which immune dysfunction in cancer can be largely ascribed. Exhausted T-cell populations during chronic infection have been observed to be heterogeneous and hyporesponsive. A plausible explanation, corroborated by recent data, for the selection of this mechanism by the evolutionary process is the prevention of tissue damage owing to overstimulation by cognate antigens, via an appropriate negative feedback loop, during chronic infections, while maintaining a good potential to control infectious agents that have successfully survived the acute phase.12 Identifying rare T-cell subtypes that emerge during chronic infection or cancer and understanding the heterogeneity of exhausted CD8+ T cells is thus expected to yield critically important new knowledge that will offer novel pharmacological intervention avenues, but these discoveries require a different methodology.

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  1. NxR Biotechnologies GmbH, Basel, Switzerland

    Alain A. Vertès

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Vertès, A.A. TOX: a rediscovered master molecular actor to enhance immuno-oncology interventions. Cell Mol Immunol 17, 558–560 (2020). https://doi.org/10.1038/s41423-019-0276-3

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