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T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosis.

ABSTRACT: Predictive biomarkers illustrating the effectiveness of chemotherapeutic regimens for tuberculosis still remain elusive. To date, most are predicated on assays using sputum or serum; as a result, if not predictive, treatment failure in patients may not be evident for some time. We report here the results of a simple screening study in which T cell surface markers were examined in mice infected with Mycobacterium tuberculosis and then treated with drugs. These studies identified certain markers, the exhaustion markers PD-1 and TIM-3, as well as the marker KLRG-1, particularly on CD8 T cells, that changed in concert with reduction of the bacterial load in the lungs. While there is no guarantee these changes would also be seen on T cells in the blood, this approach should be further investigated.

SUBMITTER: Henao-Tamayo M

PROVIDER: S-EPMC3155998 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosis.

Henao-Tamayo Marcela M Irwin Scott M SM Shang Shaobin S Ordway Diane D Orme Ian M IM

Tuberculosis (Edinburgh, Scotland) 20110429 4

Predictive biomarkers illustrating the effectiveness of chemotherapeutic regimens for tuberculosis still remain elusive. To date, most are predicated on assays using sputum or serum; as a result, if not predictive, treatment failure in patients may not be evident for some time. We report here the results of a simple screening study in which T cell surface markers were examined in mice infected with Mycobacterium tuberculosis and then treated with drugs. These studies identified certain markers, ...[more]

PMID: 21530406

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Project description:Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. The presence of CD8 tumor-infiltrating T lymphocytes (TILs) is associated with improved prognosis and therapeutic response in CRC patients. FOLFOX chemotherapy is a standard first-line treatment for patients with CRC. Yet, the effect of FOLFOX on TILs is poorly understood. Specifically, it is unclear whether FOLFOX therapy impacts the phenotype and functionality of tumor antigen specific TILs. Immune checkpoint blockade (ICB) has significantly improved clinical outcome of cancer treatment but has shown limited efficacy in CRC patients. Recently, ICB efficiency has been linked to reinvigoration of T cells with a non-terminally dysfunctional phenotype. Here, we investigate the effect of FOLFOX on CD8 T cell tumor accumulation, phenotype and function and tested the combination of FOLFOX and ICB to improve tumor regression. Methods: A mouse model of CRC expressing a human tumor antigen was used to study the effect of FOLFOX on tumor growth and TILs phenotype and function. Tetramers were used to identify and monitor phenotype and function of tumor specific TILs. The phenotype and function of TILs were compared between FOLFOX and control treatment through flow cytometry, in vivo depletion and ex vivo stimulation. Furthermore, the anti-tumor effect of the single drug or combined therapy with anti-PD1 were also assessed. Results: We show that FOLFOX treatment effectively controlled tumor burden and this was dependent on CD8 T cells. FOLFOX enabled TILs to remain in a functional differentiation state characterized by lower levels of inhibitory receptors PD-1 and TIM-3 and a CD38loCD101loTIM-3-TCF-1hi phenotype. Consistent with this, TILs from FOLFOX treated tumors exhibited higher effector function. Importantly, while anti-PD-1 treatment alone had no significant effect on tumor burden, FOLFOX and PD-1 checkpoint blockade combination showed significant tumor control. Conclusions: FOLFOX treatment impacts the phenotype and function of TILs making them more responsive to checkpoint blockade. This study highlights the importance of combining chemotherapy and ICB to optimize treatment efficacy in patients with colorectal cancer.

Dataset Information

T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosis.

Publications

T lymphocyte surface expression of exhaustion markers as biomarkers of the efficacy of chemotherapy for tuberculosis.

Similar Datasets

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