DNA mismatch repair defect and intratumor heterogeneous deficiency differently impact immune responses in diffuse large B-cell lymphoma

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 AuHarry 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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number2384667
JournalOncoImmunology
Volume13
Issue number1
DOIs
StatePublished - 2024

Keywords

  • DLBCL
  • dMMR
  • DNA mismatch repair
  • gene expression profiling
  • genomic instability
  • HDAC
  • heterogeneity
  • immune
  • MSH6
  • multiplex IHC
  • mutation
  • MYC
  • p53
  • PD-1
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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