Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade

Abstract

Anti–PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types of cancer over the past decade. The initial therapeutic hypothesis underlying the mechanism of anti–PD-1/PD-L1 ICB was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1hiCD8+ T cells by “releasing the brakes.” However, recent studies have provided unprecedented insight into the complexity within the CD8+ T-cell pool in the tumor microenvironment (TME). Single-cell RNA sequencing and epigenetic profiling studies have identified novel cell surface markers, revealing heterogeneity within CD8+ T-cell states classified as unique. Moreover, these studies highlighted that following ICB, CD8+ T-cell states within and outside the TME possess a differential capacity to respond, mobilize to the TME, and seed an effective antitumor immune response. In aggregate, these recent developments have led to a reevaluation of our understanding of both the underlying mechanisms and the sites of action of ICB therapy. Here, we discuss the evidence for the reversibility of CD8+ T-cell exhaustion after ICB treatment and its implication for the further development of cancer immunotherapy.

Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade

“…Identification of biomarkers of response to ICB relies on the understanding of the cellular and molecular mechanisms responsible for sensitivity or resistance of tumors to these therapies [ 1 ]. The adaptive T-cell response is the major target of PD-1/PD-L1 axis blockade and, understandably, most studies aiming to decipher resistance mechanisms and to identify biomarkers of response were focused on CD8 T cells, which directly recognize and kill tumor cells [ 24 ]. Whereas initial studies focused on the role of anti-PD-1/PD-L1 in reversing in situ terminal exhaustion of CD8 T cells, data obtained from preclinical tumor models and studies in cancer patients showed that responsiveness was dependent upon both reversal of exhaustion at the tumor site and proliferation of early exhausted peripheral CD8 T cells [ 4 , 24 ].…”

“…The adaptive T-cell response is the major target of PD-1/PD-L1 axis blockade and, understandably, most studies aiming to decipher resistance mechanisms and to identify biomarkers of response were focused on CD8 T cells, which directly recognize and kill tumor cells [ 24 ]. Whereas initial studies focused on the role of anti-PD-1/PD-L1 in reversing in situ terminal exhaustion of CD8 T cells, data obtained from preclinical tumor models and studies in cancer patients showed that responsiveness was dependent upon both reversal of exhaustion at the tumor site and proliferation of early exhausted peripheral CD8 T cells [ 4 , 24 ]. Expansion of peripheral CD8 T cells takes place in lymph nodes and is dependent upon CD4 help [ 16 ], inferring the importance of CD4 T cells in response to ICB.…”

Obesity modulates the immune macroenvironment associated with breast cancer development

“…Specifically, Tregs play a key role in suppressing the anti-tumoral immune response mediated by NK and CD8 + T cells [ 79 ]. In this context, recent reports have clearly shown the effectiveness of PD-1/PD-L1 checkpoint blockade in preventing anti-tumoral cytotoxic CD8+ T cell exhaustion [ 80 ] and counteracting the suppressive function of infiltrating Tregs leading to improved response to cancer therapy increase disease free survival [ 81 ]. However, in our model, Tregs were not significantly increased in tumors from obese mice ( Fig 3B and 3C ), similarly to what was observed in a previous study in melanoma [ 82 ].…”

Characterization of Ligand-Receptor Pair in Bladder Cancer Develops a Validated Scoring Model for Prognosis and Treatment Response

“…Abundance of intratumor PD-1 Treg was known to suppress anti-tumor immunity (Palucka and Coussens, 2016). In addition, high abundance of CD8+T cells at exhausted state, which was featured with high Frontiers in Cell and Developmental Biology | www.frontiersin.org their high PD-1 expression, lost the proper effector response to eliminate tumor cells (Budimir et al, 2022). Taken together, PD-1/ PD-L1 blockade could confer better immune response in the low LR.…”