PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Kim, Kyung Hwan; Kim, Hong Kwan; Kim, Hyung‐Don; Kim, Chang Gon; Lee, Hoyoung; Han, Ji Won; Choi, Seong Jin; Jeong, Seongju; Jeon, Minwoo; Kim, Hyunglae; Koh, Jai‐Kyoung; Ku, Bo Mi; Park, Su–Hyung; Ahn, Myung‐Ju; Shin, Eui‐Cheol

doi:10.1038/s41423-020-0427-6

Cited by 49 publications

(38 citation statements)

References 61 publications

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“…Our group recently reported that tumor-infiltrating CD28 + PD-1 + CD8 + T cells, which express TCF1 and retain stemness, are the population responding to PD-1 blockade ( 16 ). Based on these results, we measured the frequency of CD28 + cells among peripheral blood PD-1 + CD8 + T cells and found a decreasing trend from DCB patients to HPD patients regarding the baseline frequency of CD28 + cells among PD-1 + CD8 + T cells, but the difference was not significant ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We also evaluated the frequency of CD28 + cells among PD-1 + CD8 + T cells. Recently, our group identified that tumor-infiltrating CD28 + PD-1 + CD8 + T cells highly express TCF1 and respond to PD-1 blockade, whereas CD28 − PD-1 + CD8 + T cells are terminally exhausted and poorly respond to PD-1 blockade ( 16 ). TCF1, a Wnt family transcription factor, has been demonstrated to be a key marker of anti-PD-1 responsive T cells ( 25 26 ).…”

Section: Discussionmentioning

confidence: 99%

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Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

et al. 2020

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

et al. 2020

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“…It should be noted that similar changes are induced by human immunodeficiency virus. It was found that CD28 expression on the membrane of CD8 + T lymphocytes increases their resistance to apoptosis and antitumor activity [8]. Stimulation of CD28 expression on HSC by thymalin can reflect activation of mature T cell differentiation and antiviral immunity.…”

Section: Resultsmentioning

confidence: 99%

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

et al. 2020

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Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117 + cells into mature CD28 + T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28 + , CD4 + , CD8 + T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28 + T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

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“…Bearing in mind that the target population to revert T cell exhaustion in chronic HCV infection is the PD-1 dim memory-like precursor pool and that IL-15 promotes the development of these cells and improves their metabolic profile, the combination of PD-1 blockade plus IL-15 could be an interesting strategy to get this goal. This combination has shown to enhance CD8 T cell function in chronic viral infections [ 97 , 98 ] and also has recovered tumour-infiltrating PD-1 unresponsive CD8 T cell due to loss of CD28 [ 99 ]. Moreover, the development of CAR-T cells within a rich IL-15 environment augments the response to PD-1 blockade in solid tumours [ 100 ].…”

Section: Gamma (γ) Chain Cytokines For T Cell Exhaustion Reversionmentioning

confidence: 99%

“…In fact, tumour infiltrating CD8 + T cells are TCF1 negative and CD28 negative and do not respond to PD-1 blockade. Nevertheless, these cells still responds to IL-15 treatment, which makes them sensitive to anti-PD-1 treatment and enhanced their proliferation, probably by restoring the precursor pool [ 99 ]. Nevertheless, HCV downregulates interferon regulatory factor-2 in hepatocytes, attenuating hepatocellular expression of IL-7 and IL-15Rα to abrogate the possible benefit of these homeostatic cytokines on HCV-specific T-cell responses [ 112 ].…”

Section: Effect Of Pd-1 Modulation and γC-cytokines On Hcv-specifimentioning

confidence: 99%

Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C

Peña-Asensio

Calvo

Torralba

et al. 2021

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Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.

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PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Cited by 49 publications

References 61 publications

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells

Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C

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