PD-1⁺regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer

Abstract

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti–PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA−CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti–PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1− eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…There are inconsistencies between studies in that some have not shown age or sex to be predictors. Furthermore, although it has been described by several groups including ours , the putative genomic correlates (e.g., MDM2/MDM4 and EGFR alterations) require larger sample size validation and an understanding of potential mechanisms by which these alterations could mediate or facilitate accelerated tumor growth after checkpoint blockade.…”

Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target?

“…In line with this hypothesis, PD‐1‐deficient Treg cells possess strong immune suppressive activity and rescue autoimmune phenotypes . Anti‐PD‐1 mAb increases Treg cell‐mediated immune suppressive activity in some patients with gastric cancer, which contributes to hyperprogression during PD‐1 blockade therapy . However, another study reported that PD‐1‐blocked Treg cells show low immune suppressive activity, and further analyses to examine the roles of PD‐1 in effector T cells and Treg cells in cancer settings are needed …”

“…Programmed cell death-1 inhibits excessive activation of conventional T cells by suppressing TCR and costimulatory CD28 signaling and renders them dysfunctional or exhausted. Considering the similar expression level of PD-1 by Treg cells in the TME and the similar dependency of TCR and CD28 signaling for their survival and function, PD-1 inhibition could potentiate the activation and immunosuppressive function of Treg cells (see 5.2) 45.…”

Targeting Treg cells in cancer immunotherapy

“…This hyper‐progressive disease (HPD) with poor clinical outcome has been reported in ∼10% of cancer patients under anti‐PD‐1 mAb treatment . HPD patients showed abundant infiltration of proliferating eTreg cells into tumor tissues whereas non‐HPD patients did not . It remains to be determined how these opposite effects of PD‐1 blockade on Treg and effector Tconv cells can be controlled for better outcome, for example, by a combination with Treg‐depleting mAb, such as anti‐CCR4 and anti‐CTLA‐4 mAb.…”