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.

Figure 1. Immunity as duality of signaling, cell fate, and response dynamics.

(A) Activating signals to T cells, through anabolic metabolism induction (“feast”), drive cell division and functional differentiation (change from red to blue). Inhibitory signals oppose anabolic induction (“famine”) and functional maturation, thereby maintaining self-renewal (red). One cell can yield opposing outcomes in its daughter cells by unequal transmission of activating and inhibitory signals during cell division (color gradient in oval mitotic cell). (B) Activation, division, and differentiation (blue wedge) embody response intensity and narrowing of potential (loss of self-renewal). Self-renewing cells (red wedge) reiteratively remake themselves as they yield differentiated descendants, embodying response durability and multipotency. In the lower plot, inverse relationship between response intensity and durability is a potential vulnerability of cancer immunotherapies that focus on intensifying T cell responses in the setting of imperiled T cell durability. (C) List of mechanistic details in the duality of signaling, cell fate, metabolism, cell biology, and response dynamics. Improving immunotherapy may require creative strategies to contort the natural regenerative balance in order to optimize intensity along with greater durability.

Figure 2. Lymphocytes engaged in immunity must regenerate, which has limits.

Most hematopoiesis involves continuous production of differentiated lineages to offset continuous loss. Some capacity for facultative “tuning” of output can occur in emergencies, such as severe blood loss or infection. By contrast, lymphopoiesis generates a diverse repertoire of unique antigen receptors on individual clones (gray-outlined circles), followed by elimination of strongly autoreactive clones, and export to periphery in anticipation of immune response. In an acute or low-level persistent immune response, a sole T cell clone with correct receptor (red outline) is activated by antigenic plus costimulatory signals (collectively represented by lightning bolts), causing cell division, which is accompanied by differentiation and self-renewal by clonally related descendants of the selected cell. When the threat entails high-level, repetitive activation, at least two separable problems of failing immunity can ensue: (i) acquired dysfunction of differentiated cells, often referred to as “exhaustion,” and (ii) eroding abundance of self-renewing cells, which can result in diminished output of fresh, differentiated cells or complete loss of the clone and its descendants. It is speculated that prevention of erosion of self-renewal may be more actionable than reversal of differentiated cell dysfunction.

Figure 3. Lymphocyte differentiation stages resemble a chemical reaction.

(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. with permission.

Figure 4. Successful and insufficient immunity from a regenerative perspective.

All responses are triggered by sufficient antigen plus costimulatory signals (lightning bolt, row 1). Successful immune regeneration during acute infection and upon its resolution (row 2) illustrates the facultative (threat-dependent) nature of the progenitor and differentiated stages. Lifelong control of persistent low-level infection is analogous to perpetuation of autoimmune attack (row 3), with ongoing impetus for regeneration. Rows 4–6 depict vertical downward progression of tumor growth or increasing viral burden alongside hypothetical regenerative status without treatment (left) or with PD-1 blockade (right). The high incidence of immunotherapy resistance is probably related to progressive loss of self-renewing T cells as disease burden progresses. Optimal outcomes are more likely to be achieved when treatment is initiated earlier or with interventions that could prolong the window of self-renewing T cell abundance. Not shown is potential benefit of the arising of new neoantigens, which would appear as new red clones being deposited into the left-hand well. PD-1 blockade is depicted as lowering the activation energy and catalyzing greater division and differentiation from self-renewing cells while they persist. Adapted from ref. with permission.