Hyper-Progressive Disease: The Potential Role and Consequences of T-Regulatory Cells Foiling Anti-PD-1 Cancer Immunotherapy

Tay, Christopher; Qian, Yamin; Sakaguchi, Shimon

doi:10.3390/cancers13010048

Cited by 24 publications

(22 citation statements)

References 128 publications

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“…These findings also indicate that the combination of CCR8-targeted selective Treg depletion and immune checkpoint blockade, which aims to block negative signals to effector Tconvs, would enable a synergy in tumor immunity, as shown in this and other reports ( 36 , 37 , 39 , 49 ). Moreover, Treg depletion would prevent hyperprogressive disease (HPD), which is a rapid cancer progression occasionally observed in the course of anti–PD-1 mAb treatment ( 50 , 51 ). The occurrence of HPD is correlated well with the degree of the proliferation of PD-1 + Tregs in tumor tissues during anti–PD-1 mAb treatment; furthermore, PD-1 blockade drives Tregs to proliferate in vivo and in vitro, potentiating Treg-suppressive activity ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Kidani

Nogami

Yasumizu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8–. CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

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Section: Discussionmentioning

confidence: 99%

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Kidani

Nogami

Yasumizu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Other somatic mutations and carcinogenic pathways exist in addition to MDM2 amplification and EGFR mutations. Xiong et al [61] evaluated the mutational and transcriptional characteristics of tumors before and after anti-PD-1 immunotherapy in two patients who acquired HPD. Somatic mutations in recognized cancer genes, including tumor suppressor genes such as TSC2 and VHL, were discovered, as well as transcriptional activation of carcinogenic pathways including IGF-1, ERK/MAPK, PI3K/AKT, and TGFβ.…”

Section: Mdm2/mdm4 Amplification and Egfr Mutationmentioning

confidence: 99%

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

Ding¹,

Wen²,

Tong³

et al. 2022

CDR

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Immune checkpoint inhibitors (ICIs) are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and greatly prolonging the survival time of patients. However, not all patients can respond to ICIs, and even rapid tumor growth after treatment with ICI has been observed in a number of clinical studies. This rapid progression phenomenon is called hyper-progressive disease (HPD). The occurrence of HPD is not uncommon. Past statistics show that the incidence of HPD is 4%-29% in different tumor types, and the progression-free survival and overall survival of patients with HPD are significantly shorter than those of the non-HPD progressor group. With the deepening of the study of HPD, we have established a preliminary understanding of HPD, but the diagnostic criteria of HPD are still not unified, and the addition of biomarkers may break this dilemma. In addition, quite a few immune cells have been found to be involved in the occurrence and development of HPD in the tumor microenvironment, indicating that the molecular mechanism of HPD may be triggered by a variety of ongoing events at the same time. In this review, we summarize past findings, including case reports, clinical trials, and fundamental research; compare the diagnostic criteria, incidence, and clinical prognostic indicators of HPD in different studies; and explore the molecular mechanism and future research direction of HPD.

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“…174 The second involves the infiltration of Treg cells into tumors, due to their high level of PD-1 expression, which modulates Treg activity. 175 While blocking the inhibitory signals of PD-1 increases Treg cell activation, Treg cells may still require IL-2 for robust proliferation. 176 One may expect HPD caused by Treg cell expansion to have a shorter time to progression and to be prone to metastasis.…”

Section: Cd8 + T-cell (Ctl/killer T-cell) and T-cell Exhaustion Tils Can Be Broadly Classified As Effector Memory T-cells Central Memory mentioning

confidence: 99%

Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity

Aoki

Nishida

Kudo

2021

J Histochem Cytochem.

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Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/β-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field:

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Hyper-Progressive Disease: The Potential Role and Consequences of T-Regulatory Cells Foiling Anti-PD-1 Cancer Immunotherapy

Cited by 24 publications

References 128 publications

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity

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