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 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<sup>+</sup> T cells, higher average nearest neighbor distance between T cells and PAX5<sup>+</sup> 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<sup>+</sup> T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

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Publication Details

Journal
OncoImmunology
Published
2024-08-05
DOI
https://doi.org/10.1080/2162402x.2024.2384667
Citations
2
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.85

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article

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

Jeremy S. Abramson, Michael Møller, Cancan Luo, Karen Dybkær et al.
2 citations
OncoImmunology
Genetic factors in colorectal cancer
0.85
article

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

Jeremy S. Abramson, Michael Møller, Cancan Luo, Karen Dybkær, Ken H. Young, Govind Bhagat, Benjamin M. Parsons, Maurilio Ponzoni, Anamarija M. Perry, Xiangshan Fan, Eric D. Hsi, Zijun Y. Xu‐Monette, Ali Sakhdari, Alexandar Tzankov, Heounjeong Go, April Chiu, Youli Zu, Wayne Tam, Qingyan Au, Wenting Song, Santiago Montes‐Moreno, Dennis P. O’Malley, Harry Nunns, Andrés J.M. Ferreri, Aliyah R. Sohani, Yong Li, Yu Li, Alyssa F. Yuan, Carlo Visco, Bing Xu, N Wang
article en
2 citations

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<sup>+</sup> T cells, higher average nearest neighbor distance between T cells and PAX5<sup>+</sup> 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<sup>+</sup> T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

OncoImmunologyVol. 13(1)
University of Verona (IT), Gundersen Health System (US), Houston Methodist (US), Northwell Health (US), NewYork–Presbyterian Hospital (US), Harvard University (US), Vita-Salute San Raffaele University (IT), Baylor College of Medicine (US), University of Toronto (CA), University of Michigan (US), Aalborg University Hospital (DK), New York Hospital Queens (US), Odense University Hospital (DK), Asan Medical Center (KR), University Hospital of Basel (CH), Massachusetts General Hospital (US), Marqués de Valdecilla University Hospital (ES), Methodist Hospital (US), Instituto de Investigación Marqués de Valdecilla (ES), Mayo Clinic in Arizona (US), Duke Medical Center (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), NeoGenomics (United States) (US), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Duke Cancer Institute, Columbia University (US)
National Institutes of Health, National Cancer Institute
Zero hunger
Openalex Percentile: Top 26%
Genetic factors in colorectal cancer
0.85
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