DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma
Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the...
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2024-12-01
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2384667 |
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| author | Zijun Y. Xu-Monette Cancan Luo Li Yu Yong Li Govind Bhagat Alexandar Tzankov Carlo Visco Xiangshan Fan Karen Dybkaer Ali Sakhdari Nicholas T. Wang Alyssa F. Yuan April Chiu Wayne Tam Youli Zu Eric D. Hsi Anamarija M. Perry Wenting Song Dennis O’Malley Qingyan Au Harry Nunns Heounjeong Go Michael B. Møller Benjamin M. Parsons Santiago Montes-Moreno Maurilio Ponzoni Andrés J.M. Ferreri Aliyah R. Sohani Jeremy S. Abramson Bing Xu Ken H. Young |
| author_facet | Zijun Y. Xu-Monette Cancan Luo Li Yu Yong Li Govind Bhagat Alexandar Tzankov Carlo Visco Xiangshan Fan Karen Dybkaer Ali Sakhdari Nicholas T. Wang Alyssa F. Yuan April Chiu Wayne Tam Youli Zu Eric D. Hsi Anamarija M. Perry Wenting Song Dennis O’Malley Qingyan Au Harry Nunns Heounjeong Go Michael B. Møller Benjamin M. Parsons Santiago Montes-Moreno Maurilio Ponzoni Andrés J.M. Ferreri Aliyah R. Sohani Jeremy S. Abramson Bing Xu Ken H. Young |
| author_sort | Zijun Y. Xu-Monette |
| collection | DOAJ |
| description | Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL. |
| format | Article |
| id | doaj-art-5de2138da31648e09e4ad55f932a3cf2 |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | OncoImmunology |
| spelling | doaj-art-5de2138da31648e09e4ad55f932a3cf22025-08-20T02:50:38ZengTaylor & Francis GroupOncoImmunology2162-402X2024-12-0113110.1080/2162402X.2024.2384667DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphomaZijun Y. Xu-Monette0Cancan Luo1Li Yu2Yong Li3Govind Bhagat4Alexandar Tzankov5Carlo Visco6Xiangshan Fan7Karen Dybkaer8Ali Sakhdari9Nicholas T. Wang10Alyssa F. Yuan11April Chiu12Wayne Tam13Youli Zu14Eric D. Hsi15Anamarija M. Perry16Wenting Song17Dennis O’Malley18Qingyan Au19Harry Nunns20Heounjeong Go21Michael B. Møller22Benjamin M. Parsons23Santiago Montes-Moreno24Maurilio Ponzoni25Andrés J.M. Ferreri26Aliyah R. Sohani27Jeremy S. Abramson28Bing Xu29Ken H. Young30Hematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USADepartment of Medicine, Baylor College of Medicine, Houston, TX, USADepartment of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY, USAInstitute of Pathology, University Hospital Basel, Basel, SwitzerlandDepartment of Engineering for Innovation Medicine, Section of Hematology, University of Verona, Verona, ItalyHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAClinical Department, Aalborg University Hospital, Aalborg, DenmarkDepartment of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, CanadaHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAHematopathology Department, Mayo Clinic, Rochester, MN, USADepartment of Pathology, Northwell Health, New York, NY, USADepartment of Pathology and Genomic Medicine, The Methodist Hospital, Houston, TX, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USADepartment of Pathology, University of Michigan, Ann Arbor, MI, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USANeoGenomics Laboratories, Aliso Viejo, CA, USANeoGenomics Laboratories, Aliso Viejo, CA, USANeoGenomics Laboratories, Aliso Viejo, CA, USADepartment of Pathology, Asan Medical Center, Ulsan University College of Medicine, Seoul, South KoreaDepartment of Pathology, Odense University Hospital, Odense, DenmarkHematology & Oncology, Gundersen Lutheran Health System, La Crosse, WI, USATranslational Hematopathology Laboratory and Anatomic Pathology Service, Valdecilla/IDIVAL, UNICAN, Santander, SpainPathology Unit, Lymphoma Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyPathology Unit, Lymphoma Unit, IRCCS San Raffaele Scientific Institute, Milan, ItalyMassachusetts General Hospital, Center for Lymphoma, Harvard Medical School, Boston, MA, USAMassachusetts General Hospital, Center for Lymphoma, Harvard Medical School, Boston, MA, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USAHematopathology Division and Department of Pathology, Duke University Medical Center, Durham, NC, USADeficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.https://www.tandfonline.com/doi/10.1080/2162402X.2024.2384667DNA mismatch repairdMMRPD-1DLBCLimmuneMSH6 |
| spellingShingle | Zijun Y. Xu-Monette Cancan Luo Li Yu Yong Li Govind Bhagat Alexandar Tzankov Carlo Visco Xiangshan Fan Karen Dybkaer Ali Sakhdari Nicholas T. Wang Alyssa F. Yuan April Chiu Wayne Tam Youli Zu Eric D. Hsi Anamarija M. Perry Wenting Song Dennis O’Malley Qingyan Au Harry Nunns Heounjeong Go Michael B. Møller Benjamin M. Parsons Santiago Montes-Moreno Maurilio Ponzoni Andrés J.M. Ferreri Aliyah R. Sohani Jeremy S. Abramson Bing Xu Ken H. Young DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma OncoImmunology DNA mismatch repair dMMR PD-1 DLBCL immune MSH6 |
| title | DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma |
| title_full | DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma |
| title_fullStr | DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma |
| title_full_unstemmed | DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma |
| title_short | DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma |
| title_sort | dna mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large b cell lymphoma |
| topic | DNA mismatch repair dMMR PD-1 DLBCL immune MSH6 |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2384667 |
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