Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance

Keywords

● CD8 T cells

● Tumour-draining lymph node

● Stem-like T cells

● Lymphatic egress

● Immune checkpoint blockade

Main Findings

Effector CD8 T cells are crucial in driving robust anti-tumour immunity but are often lost to dysfunction from chronic antigen stimulation in the tumour microenvironment (TME). What sustains the response is a pool of self-renewing stem-like CD8 T cells in the tumour draining lymph node (TdLN). The Lund group (Steele et al.) has previously shown that a population of PD-1lo/mid effector CD8+ T cells egress the TME, and that limiting this exit improves the quality and quantity of CD8 T cells and response to ICB. But why would effector T cells egress out of an environment that has their cognate antigen, and what is their fate? A preprint (not peer reviewed) from the same group by Delclaux et al. set out to answer this question.

The authors used a Kaede-transgenic photoconvertible mouse to timestamp immune cells in the tumour. Single-cell RNA-sequencing 24h after photoconversion revealed that photoconverted T cells in the tumour were more interferon-responsive, dysfunctional and proliferating whereas those in the TdLNs were more stem-like and memory-like. Most intriguing was the presence of a larger number of stem-like photoconverted T cells in the TdLNs than in the tumour itself, raising the possibility that stemness was induced after arrival in the TdLNs. Furthermore, the authors found that photoconverted effector T cells in the TdLNs had higher levels of the stem cell marker TCF1 at 24h than at 12h. As all the immune cells were labelled at the same time, this implies that effector CD8+T cells do not leave the tumour in a stem-like state but become stem-like over time in the TdLN.

Steele et al. proposed that tumour egress might allow for T cells to escape chronic antigen stimulation, thereby preserving stemness and antitumour function. Delclaux et al. go beyond this and test whether antigen re-encounter in the TdLNs has a role in inducing the stem-like state and which antigen-presenting cell might be responsible. Using bilateral flank tumour models, with tumour resection to cut antigen drainage to the TdLN and depletion of CD11c+ cells, they identify a self-sustaining loop by which dendritic cells recirculate tumour antigen to the TdLNs to re-engage egressed effector T cells that have re-expressed TCF1. This regenerated stem-like T cell pool in the TdLNs continuously seeds the tumour with effector cells, thereby sustaining the antitumour response.

Breaking this tumour–TdLN circuit has clinical implications. First, it may explain why patients with lymph node metastases, which could impair the stem-like T cell pool, respond poorly to ICB. Second, it suggests that tumour resection before ICB may deprive the stem-like T cells of the antigen presentation they require.

Limitations

- They never close the loop: The authors show T cells leaving the tumor and becoming stem-like in the TdLN, but the return of stem-like T cells making effectors that traffic back and control the tumor is mainly inferred from the prior work. The model put forth is continuous tumor-LN loop requirement, but the presented experiments highlight only one part of the loop.

- T cell recycling and antigen supply aren’t separated: Resection of tumor to show antigen draining in LN important for inducing stem-like T cells, removes two things at once: T cell egress and antigen drainage to the lymph node. Between these two, what drives the collapse of stem-like T cells in LN is not looked into independently. Could antigen draining alone in the LN keep the pool of stem-like T cells restored at all time point, or is the recycling of T cells from tumor to LN and back is absolutely necessary? An experiment blocking T cell egress while keeping the antigen flow isn’t done.

- Tested in immunogenic model- The circuit is established in an immunogenic melanoma model using OVA and high affinity OT-1 TCR, so the conversion is only shown in strong antigen environment. There is an outstanding question of whether the strength TCR reengagement in the LN somehow dictates TCF-1 re-expression and stem-like induction. It remains unclear whether weaker or low affinity antigens, closer to most physiological neoantigens, can still induce and sustain this loop. It would thus be of interest to validate these findings in poorly immunogenic and cold tumor models.

Significance/Novelty

This preprint uncovers an important effector T cell recirculation circuit that maintains a systemic anti-tumor response. Rather than looking at functional T cell egress from TME as a loss, it establishes a circuit that helps in maintenance of stem-like pool in the LN. The findings have strong translational value as they can help in making informed decisions around timing of ICB and tumor resection, since antigen drainage to the LN appears crucial for maintenance of stem-like T cell pool. It also offers a basis for why neoadjuvant therapy sometimes outperforms adjuvant therapy, and why LN metastasis predicts poor response to ICB.

Credit

Reviewed by Sandhya Yadav as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.