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Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8⁺ T Cell Exhaustion Marker Expression.

ABSTRACT: In untreated HIV infection, CD8⁺ T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8⁺ T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8⁺ T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n?=?19 (Early ART) and n?=?23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8⁺ T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8⁺ T cell-based therapies to treat HIV, for which CD8⁺ T cell exhaustion remains an important barrier to efficacy.

SUBMITTER: Rutishauser RL

PROVIDER: S-EPMC5512309 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8+ T Cell Exhaustion Marker Expression.

Rutishauser Rachel Lena RL Hartogensis Wendy W Deguit Christian Deo CD Krone Melissa M Hoh Rebecca R Hecht Frederick M FM Pilcher Christopher D CD Bacchetti Peter P Deeks Steven G SG Hunt Peter W PW McCune Joseph M JM

AIDS research and human retroviruses 20170425 7

In untreated HIV infection, CD8+ T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8+ T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustio ...[more]

PMID: 28335609

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Project description:BackgroundChimeric antigen receptor (CAR) T-cell therapy is an emerging option for cancer treatment, but its efficacy is limited, especially in solid tumors. This is partly because the CAR T cells become dysfunctional and exhausted in the tumor microenvironment. However, the key pathways responsible for impaired function of exhausted cells remain unclear, which is essential to overcome CAR T-cell exhaustion.MethodsAnalysis of RNA-sequencing data from CD8+ tumor-infiltrating lymphocytes (TILs) led to identification of Cbl-b as a potential target. The sequencing data were validated using a syngeneic MC38 colon cancer model. To analyze the in vivo role of Cbl-b in T-cell exhaustion, tumor growth, % PD1+Tim3+ cells, and expression of effector cytokines were analyzed in cbl-b+/+ and cbl-b-/- mice. To evaluate the therapeutic potential of Cbl-b depletion, we generated a new CAR construct, hCEAscFv-CD28-CD3?.GFP, that recognizes human carcinoembryonic antigen (CEA). cbl-b+/+ and cbl-b-/- CEA-CAR T cells were generated by retroviral transduction. Rag -/- mice bearing MC38-CEA cells were injected with cbl-b+/+ and cbl-b-/- ; CEA-CAR T cells, tumor growth, % PD1+Tim3+ cells and expression of effector cytokines were analyzed.ResultsOur results show that the E3 ubiquitin ligase Cbl-b is upregulated in exhausted (PD1+Tim3+) CD8+ TILs. CRISPR-Cas9-mediated inhibition of Cbl-b restores the effector function of exhausted CD8+ TILs. Importantly, the reduced growth of syngeneic MC38 tumors in cbl-b-/- mice was associated with a marked reduction of PD1+Tim3+ CD8+ TILs. Depletion of Cbl-b inhibited CAR T-cell exhaustion, resulting in reduced MC38-CEA tumor growth, reduced PD1+Tim3+ cells and increased expression of interferon gamma, tumor necrosis factor alpha, and increased tumor cell killing.ConclusionOur studies demonstrate that deficiency of Cbl-b overcomes endogenous CD8+ T-cell exhaustion, and deletion of Cbl-b in CAR T cells renders them resistant to exhaustion. Our results could facilitate the development of efficient CAR T-cell therapy for solid tumors by targeting Cbl-b.

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Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8⁺ T Cell Exhaustion Marker Expression.

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Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8<sup>+</sup> T Cell Exhaustion Marker Expression.

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