Dataset Information

Enhancing antitumor immunity through checkpoint blockade as a therapeutic strategy in T-cell lymphomas.

ABSTRACT: The majority of historical therapies for managing T-cell lymphomas (TCLs) have consisted of T-cell-depleting strategies. Unfortunately, these forms of therapies can hamper the ability to mount effective antitumor immune responses. Recently, the use of checkpoint inhibitors has revolutionized the therapy of solid and hematologic malignancies. The development of immunotherapies for the management of TCL has lagged behind other malignancies given 2 central reasons: (1) the competing balance of depleting malignant T cells while simultaneously enhancing an antitumor T-cell response and (2) concern for tumor hyperprogression by blocking inhibitory signals on the surface of the malignant T cell, thereby leading to further proliferation of the malignant cells. These challenges were highlighted with the discovery that programmed cell death protein 1 (PD-1) functions paradoxically as a haploinsufficient tumor suppressor in preclinical TCL models. In contrast, some preclinical and clinical evidence suggests that PD-1/programmed death ligand 1 may become an important therapeutic tool in the management of patients with TCL. Improved understanding of the immune landscape of TCL is necessary in order to identify subsets of patients most likely to benefit from checkpoint-inhibitor therapy. With increased preclinical research focus on the tumor microenvironment, substantial strides are being made in understanding how to harness the power of the immune system to treat TCLs. In this review, designed to be a "call to action," we discuss the challenges and opportunities of using immune-modulating therapies, with a focus on checkpoint inhibitors, for the treatment of patients with TCL.

SUBMITTER: Neuwelt A

PROVIDER: S-EPMC7479955 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Enhancing antitumor immunity through checkpoint blockade as a therapeutic strategy in T-cell lymphomas.

Neuwelt Alexander A Al-Juhaishi Taha T Davila Eduardo E Haverkos Bradley B

Blood advances 20200901 17

The majority of historical therapies for managing T-cell lymphomas (TCLs) have consisted of T-cell-depleting strategies. Unfortunately, these forms of therapies can hamper the ability to mount effective antitumor immune responses. Recently, the use of checkpoint inhibitors has revolutionized the therapy of solid and hematologic malignancies. The development of immunotherapies for the management of TCL has lagged behind other malignancies given 2 central reasons: (1) the competing balance of depl ...[more]

PMID: 32898250

Similar Datasets

Project description:BACKGROUND:Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation of patients developed hyperprogressive disease upon PD-1 blockade therapy. Combination therapy with targeted agents may improve immunotherapy. Recent studies show that p53 activation in the myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development and invasion, leading to the hypothesis that p53 activation may augment antitumor immunity elicited by anti-PD-1 therapy. METHOD:Using APG-115 that is a MDM2 antagonist in clinical development as a pharmacological p53 activator, we investigated the role of p53 in immune modulation and combination therapy with PD-1 blockade. RESULTS:In vitro treatment of bone marrow-derived macrophages with APG-115 resulted in activation of p53 and p21, and a decrease in immunosuppressive M2 macrophage population through downregulation of c-Myc and c-Maf. Increased proinflammatory M1 macrophage polarization was observed in the spleen from mice treated with APG-115. Additionally, APG-115 has co-stimulatory activity in T cells and increases PD-L1 expression in tumor cells. In vivo, APG-115 plus anti-PD-1 combination therapy resulted in enhanced antitumor activity in Trp53wt, Trp53mut, and Trp53-deficient (Trp53-/-) syngeneic tumor models. Importantly, such enhanced activity was abolished in a syngeneic tumor model established in Trp53 knockout mice. Despite differential changes in tumor-infiltrating leukocytes (TILs), including the increases in infiltrated cytotoxic CD8+ T cells in Trp53wt tumors and M1 macrophages in Trp53mut tumors, a decrease in the proportion of M2 macrophages consistently occurred in both Trp53wt and Trp53mut tumors upon combination treatment. CONCLUSION:Our results demonstrate that p53 activation mediated by APG-115 promotes antitumor immunity in the tumor microenvironment (TME) regardless of the Trp53 status of tumors per se. Instead, such an effect depends on p53 activation in Trp53 wild-type immune cells in the TME. Based on the data, a phase 1b clinical trial has been launched for the evaluation of APG-115 in combination with pembrolizumab in solid tumor patients including those with TP53mut tumors.

Dataset Information

Enhancing antitumor immunity through checkpoint blockade as a therapeutic strategy in T-cell lymphomas.

Publications

Enhancing antitumor immunity through checkpoint blockade as a therapeutic strategy in T-cell lymphomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets