Immune regeneration: implications for cancer immunotherapy and beyond
Steven L. Reiner
Steven L. Reiner
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Immune regeneration: implications for cancer immunotherapy and beyond

Abstract

Cancer care is being transformed by therapies leveraging T lymphocytes to attack tumor cells. In parallel, recent basic discoveries have converged into a framework of lymphocyte-dependent immunity as a regenerative process that is sometimes outstripped by high-level engagement. In a stem cell–like fashion, selected T cells must balance mutually opposing demands of differentiation and self-renewal. Activating versus inhibitory signals to T cells instruct opposing cell metabolism, linked to alternative cell fates that arise in sibling cells through lopsided information transfer. Emerging studies indicate that durable immunotherapy response may be limited by the abundance of self-renewing T cells. Leveraging of basic discoveries of regenerative signaling to bolster sustained, stem-like output of freshly differentiated T cells is offering new strategies to overcome cancer immunotherapy resistance. Lymphocyte regeneration may also sustain harmful autoimmune attack. Undercutting the self-renewal of pathogenic clones may thus emerge as a therapeutic strategy for autoimmune diseases.

Authors

Steven L. Reiner

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Figure 3

Lymphocyte differentiation stages resemble a chemical reaction.

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Lymphocyte differentiation stages resemble a chemical reaction. (A) Hypo...
(A) Hypothetical reaction progress wherein reactants are quiescent precursors (red cell) at low stable energy level plus the stimuli of antigen and costimulatory signals (together represented by lightning bolt), resulting in PI3K activation, anabolic induction, and cell division with ascent of some progeny to the energetic transition state. The unstable intermediate (purple, progenitor cells) with further activation (lightning bolt) and cell division yields the product (blue, irreversibly differentiated cells), which has absorbed energy to a stable, somewhat higher level than the precursor, and silencing of TCF1 (TCF1–) by virtue of PI3K’s inactivation of FoxO1, an obligatory guardian of TCF1 expression. Inhibitory signals to T cells are thought to support the threshold of activation energy required for reaction progress. (B) The unstable intermediate (progenitor) at peak energy levels represents a facultative, hybrid state. Under continued stimulation it is anabolic, with gene expression resembling that of effector cells, yet not committed to differentiation. Upon pathogen clearance, the progenitor reverts (rolls backward downhill) to the gene expression and homing patterns of the quiescent precursor fate when there is no longer an active need to yield the product. (C) Schematic of three stages indicating which stages are reversible or unidirectional (top portion) and where asymmetric division results in sibling cells with opposing outcomes (bottom portion), undertaking forward progression (straight arrow) while staying in place (backward looping arrow). Asymmetric divisions begin with interphase polarity following activation (not shown), giving way to mitotic polarity (color gradient), resulting in unequal transmission of PI3K signaling during division (bicolored sibling pair). Adapted from ref. 13 with permission.