CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita; Wyatt, Megan; Dhar, Payal; Selvam, Shanmugam Panneer; Fu, Jianing; Zhang, Jinyu; Nguyen, Hung; Kang, In-Hong; Toth, Kyle; Al-Homrani, Mazen; Husain, Mahvash; Beeson, Gyda; Ball, Lauren E.; Helke, Kristi L.; Husain, Shahid; Garrett‐Mayer, Elizabeth; Hardiman, Gary; Mehrotra, Meenal; Nishimura, Michael I.; Beeson, Craig C.; Bupp, Melanie Gubbels; Wu, Jennifer D.; Öğretmen, Besim; Paulos, Chrystal M.; Rathmell, Jeffery C.; Yu, Xue-Zhong; Mehrotra, Shikhar

doi:10.1016/j.cmet.2017.10.006

Cited by 215 publications

(258 citation statements)

References 58 publications

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“…This is important to note, given that recent studies have spoken to the varied functional status of both peripheral blood and BM T cells from multiple myeloma patients (40,41). Moreover, these findings align with work conducted by Chatterjee et al, which showed that inhibition of CD38 increased NAD + -dependent activity of Sirt1 and enhanced the anti-tumor effect of CD8 + T cells (42). Since the majority of our samples were from WB, we investigated this aspect of T-cell biology for markers associated with CD8 + T-cell exhaustion and showed that the median percentage of PD1 + CD8 + T cells trended downward in responders but tended to increase in non-responders (both not significant).…”

Section: Discussionsupporting

confidence: 85%

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

et al. 2018

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Daratumumab is a CD38‐targeted human monoclonal antibody with direct anti‐myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T‐cell expansion and reduction of immune‐suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in‐depth analysis of the effects of daratumumab on immune‐cell subpopulations using high‐dimensional mass cytometry. Whole‐blood and bone‐marrow baseline and on‐treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high‐throughput immunophenotyping. In daratumumab‐treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole‐blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune‐suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38 + basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T‐cell population in whole‐blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity ( P = 0.017), suggesting increased killing capacity and supporting monotherapy‐induced CD8 + T‐cell activation. High‐throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B + T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

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Section: Discussionsupporting

confidence: 85%

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

et al. 2018

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“…NAD + is central to mitochondrial energy metabolism, and it also serves as a substrate for Sirtuin family members regulated deacetylation reaction and PARP family members mediated ADP-ribosylation 36,37,51-53 . It was previously reported that a NAD + -Sirt1-Foxo1 axis controls the anti-tumor potential of hybrid Th1/17 cells generated from ex vivo cultures 54 . In contrast to this role of NAD + as a substrate for deacetylation and ADP-ribosylation, we here discovered that NAD + can control T cell activation via regulation of energy metabolism.…”

Section: Main Textmentioning

confidence: 99%

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺supplementation

Wang

et al. 2020

Preprint

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Tumor immunotherapies have provided clinical benefits, yet great potential remains for optimizing therapeutic effects. Here, we show that low NAD + levels restrict the function of 20 tumor infiltrating T lymphocytes (TILs). TILs harvested from human ovarian tumor tissues showed decreased NAD + levels compared with T cells from paired peripheral blood samples.The combination of whole-genome CRISPR and large-scale metabolic inhibitor screens implicated the NAD + biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. Further isotopic labeling and LC-MS studies confirmed that NAD + 25 depletion suppressed mitochondrial energy biosynthesis in T cells. Excitingly, NAD + supplementation significantly enhanced the tumor cell-killing efficacy of CAR-T cells ex vivo, and extended animal survive in both adoptive CAR-T model and immune checkpoint blockade treatment models in vivo. This study demonstrates an over-the-counter nutrient supplement NAD + could robustly boost the efficacy of T cell-based immunotherapy and provides insights 30 into the cellular basis of T cell metabolic reprogramming in treating cancers. One Sentence Summary:NAD + supplementation during cancer immunotherapies significantly enhances T cell activation and tumor killing capacity.Main Text: 35 Cancer immunotherapies including adoptive transfer of naturally-occurring tumor infiltrating lymphocytes (TIL) and genetically-engineered T cells, as well as the use of immune checkpoint inhibitors to boost the function of T cells have emerged as promising approaches to achieve durable clinical responses of otherwise treatment-refractory cancers 1-5 . Although cancer immunotherapies have been successfully utilized in the clinic for subsets of patients, there are 40 several limitations which prevent the broad use of these therapies for entire patient populations 6,7 . Given the function of T cells as key mediators for tumor destruction, their characteristics (e.g., durability, longevity, and killing efficiency, etc.) substantially determine the clinical outcomes of many immunotherapies [8][9][10][11] . Studies have established that successful clearance of tumors mediated by infiltrated T cells can be limited by physical barriers generated by stroma 45 3 cells 12 , immuno-suppressive networks 13 , and nutrient limitations within the microenvironment 14,15 . Thus, efforts to promote the stemness, proliferation and activation capacity of T cells should enable improvements to the efficacy of cancer immunotherapies.Recently, cellular metabolic processes have been reported to shape T cell differentiation and functional activity [16][17][18] . Modulation of metabolic process such as fatty acid catabolism can 50 improve T cell activation and therapeutic function [19][20][21][22][23][24] . It was also reported that there is a strong link between metabolic activity in tumor infiltrated T cells (TIL) and their effector function 25,26 , and stimulation mitochondrial biogenesis via enforced expression of PGC1α resulted in...

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“…Previous studies have reported that CD38 regulates immune cell homing, innate immune responses to pathogens, and anti-tumor immunity [76][77][78] . However, Cd38 remains a largely uncharacterized gene in immunology, despite its widespread use in the field as an activation marker.…”

Section: Discussionmentioning

confidence: 99%

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38⁺pro-inflammatory macrophages

Covarrubias

López-Domínguez

Perrone

et al. 2019

Preprint

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Decline in tissue NAD levels during aging is linked to aging and its associated diseases. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1-like macrophages, but not naïve or M2 macrophages, accumulate in metabolic tissues including visceral white adipose tissue and the liver during aging. Remarkably, these M1-like macrophages highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. We also find that senescent cells progressively accumulate in visceral white adipose tissue during aging and that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induce macrophages to proliferate and to express CD38. These results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and represent a novel therapeutic opportunity targeting maintenance of NAD levels during aging. Introduction:Nicotinamide adenine dinucleotide (NAD) is a redox coenzyme central to energy metabolism and an essential cofactor for non-redox NAD-dependent enzymes including sirtuins and poly-ADP-ribose polymerases (PARPs) 1 . Early in the 20 th century, NAD deficiency was linked to pellagra, a disease characterized by dermatitis, diarrhea, dementia, and eventually death 2 . More recently, a progressive decrease in NAD levels during aging in both rodents and humans has been documented in multiple tissues including the liver, adipose tissue, and muscle 3 . Remarkably, restoration of NAD levels with the NAD precursor vitamins nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA), in addition to the biosynthetic NAD precursor nicotinamide mononucleotide (NMN) appear to mitigate aging-associated diseases 3-5 . These observations have stimulated a flurry of research activity aiming to better understand how NAD levels affect the aging process and how or why NAD levels decline during aging, with the goal of developing therapeutics to combat aging-related disease.

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CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Cited by 215 publications

References 58 publications

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺supplementation

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38⁺pro-inflammatory macrophages

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CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Cited by 215 publications

References 58 publications

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

High‐Parameter Mass Cytometry Evaluation of Relapsed/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD+supplementation

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38+pro-inflammatory macrophages

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Potentiating the anti-tumor response of tumor infiltrated T cells by NAD⁺supplementation

Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38⁺pro-inflammatory macrophages