CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

Chen, Limo; Diao, Lixia; Yang, Yongmei; Yi, Xiaohui; Rodriguez, B. Leticia; Li, Yanli; Villalobos, Pamela; Cascone, Tina; Liu, Xi; Tan, Lin; Lorenzi, Philip L.; Huang, Anfei; Zhao, Qiang; Peng, Di; Fradette, Jared J.; Peng, David H.; Ungewiss, Christin; Roybal, Jonathon D.; Tong, Pan; Oba, Junna; Skoulidis, Ferdinandos; Peng, Weiyi; Carter, Brett W.; Fan, You-Hong; Class, Caleb A.; Zhu, Jingfen; Rodriguez‐Canales, Jaime; Kawakami, Masanori; Byers, Lauren A.; Woodman, Scott E.; Papadimitrakopoulou, Vassiliki A.; Dmitrovsky, Ethan; Wang, Jing; Ullrich, Stephen E.; Wistuba, Ignacio I.; Heymach, John V.; Qin, F. Xiao-Feng; Gibbons, Don L.

doi:10.1158/2159-8290.cd-17-1033

Cited by 349 publications

(457 citation statements)

References 50 publications

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“…Antagonizing A2AR or inhibiting CD73 has synergistic effects against tumors when combined with anti‐PD‐1 . Furthermore, a recent study showed that resistance to PD‐L1 blockade in mouse models of non‐small cell lung cancer was associated with enhanced expression of CD38 by tumor cells and A2AR‐induced immune suppression . Consistent with an important role for CD38 expression in mediating tumor escape, CD38, or A2AR antagonists enhanced the therapeutic effects of anti‐PD‐L1.…”

Section: Targeting the Tumor Microenvironment To Improve Immunotherapiesmentioning

confidence: 90%

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Hope

Salmond

2019

Eur J Immunol

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The successful implementation of immunotherapies has provided new impetus in the fight against cancer. Antibody‐mediated blockade of immune checkpoint molecules PD‐1/PD‐L1 and CTLA‐4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, while adoptive cell therapies using chimeric antigen receptor‐bearing T cells have proven highly efficacious in B cell leukemia. Furthermore, significant progress has been made in understanding the mechanisms by which tumors evade or become resistant to these immunotherapies. In this regard, approaches to broaden the applicability and enhance the efficacy of immunotherapies increasingly include modulation of tumor and immune cell metabolism. In this mini‐review, we highlight the most recent studies describing novel approaches and targets for the manipulation of the tumor microenvironment and T cell metabolism and describe how these approaches are being combined with current immunotherapies in preclinical studies.

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Section: Targeting the Tumor Microenvironment To Improve Immunotherapiesmentioning

confidence: 90%

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Hope

Salmond

2019

Eur J Immunol

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“…However, checkpoint blockade as the treatment of MSS CRC is unsuccessful. Moreover, although treatment with immune checkpoint inhibitors provides promising benefits for patients with cancer, the optimal use is encumbered by high resistance rates and requires thorough understanding of the resistance mechanisms . Our results showed that CD38 is overexpressed in PD‐1+ T cells from patients with CRC.…”

Section: Discussionmentioning

confidence: 80%

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

Liu

Fan

et al. 2020

Intl Journal of Cancer

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The majority of patients with microsatellite stable (MSS) colorectal cancer (CRC) do not benefit from the immunotherapies directed at rescuing T‐cell functions. Therefore, complete understanding of T‐cell phenotypes and functional status in the CRC microenvironment is desirable. Here, we applied single‐cell mass cytometry to mold the T‐cell phenotype in 18 patients with MSS CRC for better understanding of CRC as a systemic disease and to search for tumor‐driven T‐cell profile changes. We show interpatient and intrapatient phenotypic diversity of T‐cell subsets. We revealed increased immunosuppressive/exhausted T‐cell phenotypes at tumor lesions. CD8+ CD28− immunosenescent T cells with impaired proliferation capacity dominate the T‐cell compartment. As per the transcriptome and quantitative real time‐PCR analysis, the accumulation of immunosuppressive cells is driven by the tumor microenvironment. T‐cell profiles are similar between patients at early and late stages, indicating that the immunosuppressive microenvironment is formulated early during CRC development. Mapping of T‐cell infiltration and understanding of the mechanisms underlying their regulation may provide valuable information to boost the immune response in patients with MSS CRC.

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“…Therefore, the decreased number of pDC associated with the use of Dara suggests an additional mechanism of action of Dara through pDC depletion. Recently, Chen et al demonstrated that CD38 upregulation in tumors induces resistance to PD‐1/PD‐L1 blocking antibodies and coinhibition of CD38 and PD‐L1 improves antitumor immune response. Several studies have shown that PD‐L1 is expressed on plasma cells but also on DC in the bone marrow, with a various intensity of PDL‐1 expression among patients .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Chen et al demonstrated that CD38 upregulation in tumor induces resistance to programmed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) blocking antibodies and coinhibition of CD38 and PD‐L1 improves antitumor immune responses. This mechanism of immune resistance caused by CD38 provides an evident rationale to evaluate immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

et al. 2020

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Background Daratumumab (Dara), an anti‐CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells. Methods We analyzed CD38 and PD‐L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara. Results We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well‐known rapid depletion of natural killer cells. Finally, we found that PD‐L1 expression on antigen‐presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase. Conclusion Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD‐L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD‐L1/PD‐1 pathway in patients with MM.

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CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade

Cited by 349 publications

References 50 publications

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

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