Cell-Intrinsic CD38 Expression Sustains Exhausted CD8
            <sup>+</sup>
            T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection

DeRogatis, Julia M.; Neubert, Emily N.; Viramontes, Karla M.; Henriquez, Monique L.; Nicholas, Dequina; Tinoco, Roberto

doi:10.1128/jvi.00225-23

Cited by 10 publications

(8 citation statements)

References 57 publications

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“…However, the study, in contrast to our findings, showed that CD38 deletion in LCMV-specific CD8 + T cells resulted in a modest but significant decrease in the frequency of TCF1 + Tpex cells during chronic LCMV Cl13 infection ( 38 ). We propose that the reduced frequency of TCF1 + P14 + T cells upon CD38 deletion may not be attributed to the decreased expression of TCF1 but instead to increased proliferation and subsequent differentiation of TCF1 + Tpex cells into highly effector TCF1 - PD1 + Tex cells, as observed earlier in the case of chronic LCMV infection ( 12 , 38 , 39 ). Therefore, it is possible that CD38 −/− LCMV-specific P14 + T cells, compared to wild-type P14 + T cells, had high TCF1 expression on a per-cell basis, triggering their massive expansion and differentiation into the effector subset upon antigen encounter in mice, while maintaining a small pool of TCF1 + P14 + T cells ( 12 , 39 ).…”

Section: Discussioncontrasting

confidence: 99%

“…Congruently, we also observed that the dysfunctionality of Tex cells, in terms of their cytokine production, could partially be rescued by blocking CD38, suggesting the role of CD38 in regulating the functional fate of the T cells ( 17 ). The role of CD38 in regulating effector cytokine production by Tex has also been demonstrated in mice with chronic LCMV infection ( 38 ). However, the study, in contrast to our findings, showed that CD38 deletion in LCMV-specific CD8 + T cells resulted in a modest but significant decrease in the frequency of TCF1 + Tpex cells during chronic LCMV Cl13 infection ( 38 ).…”

Section: Discussionmentioning

confidence: 94%

“…The role of CD38 in regulating effector cytokine production by Tex has also been demonstrated in mice with chronic LCMV infection ( 38 ). However, the study, in contrast to our findings, showed that CD38 deletion in LCMV-specific CD8 + T cells resulted in a modest but significant decrease in the frequency of TCF1 + Tpex cells during chronic LCMV Cl13 infection ( 38 ). We propose that the reduced frequency of TCF1 + P14 + T cells upon CD38 deletion may not be attributed to the decreased expression of TCF1 but instead to increased proliferation and subsequent differentiation of TCF1 + Tpex cells into highly effector TCF1 - PD1 + Tex cells, as observed earlier in the case of chronic LCMV infection ( 12 , 38 , 39 ).…”

Section: Discussionmentioning

confidence: 94%

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CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

Kar,

Ghosh,

Gautam

et al. 2024

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

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PD1 blockade therapy, harnessing the cytotoxic potential of CD8 + T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8 + T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8 + T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8 + T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8 + T cells, revealed that CD38-expressing CD8 + T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8 + T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8 + T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8 + T cells elevated intracellular Ca 2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8 + T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

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CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

Kar,

Ghosh,

Gautam

et al. 2024

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

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“…Similar to PDCD1 (encoding PD-1) and ENTPD1 (encoding CD39), the CD38 locus is open in exhausted T cells in cancer and chronic viral infection 13,43 . Interestingly, studies in patients with hepatitis C virus (HCV) confirmed high expression of CD38 in the setting of chronic viral infection, and demonstrated normalisation of CD38 expression following effective antiviral therapy 44,45 , in contrast to ENTPD1 and PDCD1 whose elevated expression is maintained even after successful viral clearance, suggesting permanent epigenetic scarring 40 . Thus, despite the strong co-expression of CD38 with PDCD1 (PD-1), ENTPD1 (CD39), and other putative exhaustion markers, the factors governing up- and -downregulation of CD38 and extent of reversibility will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Revach,

Cicerchia,

Shorer

et al. 2024

Preprint

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A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

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“…As mentioned above, HLA-DR + CD8 + T-cells might have regulatory functions and express exhaustion markers. A recent study in mice showed that CD38 + CD8 + T-cells present during an acute or chronic infections can also expressed the exhaustion marker PD-1 and that CD38 expression, especially during a chronic CMV infection, lowered Granzyme B production and proliferation of the T-cells while supporting survival of these cells 27 . Potentially, the role of these HLA-DR + and/or CD38 + T-cells is to suppress immune responses during chronic infection.…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus and Epstein–Barr virus co-infected young and middle-aged adults can have an aging-related T-cell phenotype

Hofstee

Cevirgel

Zeeuw-Brouwer

et al. 2023

Sci Rep

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Cytomegalovirus (CMV) is known to alter circulating effector memory or re-expressing CD45RA+ (TemRA) T-cell numbers, but whether Epstein–Barr virus (EBV) does the same or this is amplified during a CMV and EBV co-infection is unclear. Immune cell numbers in blood of children and young, middle-aged, and senior adults (n = 336) were determined with flow cytometry, and additional multivariate linear regression, intra-group correlation, and cluster analyses were performed. Compared to non-infected controls, CMV-seropositive individuals from all age groups had more immune cell variance, and CMV+ EBV− senior adults had more late-differentiated CD4+ and CD8+ TemRA and CD4+ effector memory T-cells. EBV-seropositive children and young adults had a more equal immune cell composition than non-infected controls, and CMV− EBV+ senior adults had more intermediate/late-differentiated CD4+ TemRA and effector memory T-cells than non-infected controls. CMV and EBV co-infected young and middle-aged adults with an elevated BMI and anti-CMV antibody levels had a similar immune cell composition as senior adults, and CMV+ EBV+ middle-aged adults had more late-differentiated CD8+ TemRA, effector memory, and HLA-DR+ CD38− T-cells than CMV+ EBV− controls. This study identified changes in T-cell numbers in CMV- or EBV-seropositive individuals and that some CMV and EBV co-infected young and middle-aged adults had an aging-related T-cell phenotype.

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Cell-Intrinsic CD38 Expression Sustains Exhausted CD8 ⁺ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection

Abstract: Our study shows how CD38 expression is regulated on CD8 + T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8 + T cells during chronic viral infection compared to levels during acute viral infection.

Cited by 10 publications

References 57 publications

CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Cytomegalovirus and Epstein–Barr virus co-infected young and middle-aged adults can have an aging-related T-cell phenotype

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Cell-Intrinsic CD38 Expression Sustains Exhausted CD8 + T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection

Abstract: Our study shows how CD38 expression is regulated on CD8 + T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8 + T cells during chronic viral infection compared to levels during acute viral infection.

Cited by 10 publications

References 57 publications

CD38–RyR2 axis–mediated signaling impedes CD8 + T cell response to anti-PD1 therapy in cancer

CD38–RyR2 axis–mediated signaling impedes CD8 + T cell response to anti-PD1 therapy in cancer

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Cytomegalovirus and Epstein–Barr virus co-infected young and middle-aged adults can have an aging-related T-cell phenotype

Contact Info

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Resources

About

Cell-Intrinsic CD38 Expression Sustains Exhausted CD8 ⁺ T Cells by Regulating Their Survival and Metabolism during Chronic Viral Infection

CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer

CD38–RyR2 axis–mediated signaling impedes CD8 ⁺ T cell response to anti-PD1 therapy in cancer