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Immune evasion phenotype is common in Richter transformation diffuse large B-cell lymphoma variant

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Abstract

Immune checkpoint inhibitors (PD-1 inhibitors) have shown clinical activity in Richter transformation-diffuse large B-cell lymphoma variant (RT-DLBCL), thus providing for a novel therapeutic approach. The study group consists of 64 patients with RT-DLBCL. Expression of PD-1, PD-L1, CD30, and microsatellite instability (MSI) status (hMLH1, hMSH2, hMSH6, PMS1) was assessed using immunohistochemistry. EBV-encoded RNA (EBER) was evaluated using colorimetric in situ hybridization. PD-1 and PD-L1 expression levels were categorized on the basis of tumor cell expression as follows: negative (< 5%), positive to low-positive (5–50%), or high-positive (> 50%). An “immune evasion phenotype” (IEP) was defined as RT-DLBCL cases having high-positive expression of PD-1 and/or PD-L1 on tumor cells. The level of PD1-positive tumor-infiltrating lymphocytes (TILs) was estimated as a fraction of total lymphocytes and categorized as negative/low vs. brisk (> 20%). 28/64 (43.7%) patients were characterized as IEP+ RT-DLBCL. A brisk level of PD1+ TILs was significantly more common in IEP1+ compared with IEP- tumors (17/28, 60.7% vs. 5/34, 14.7%; p = 0.001). In addition, CD30 expression was significantly more common in IEP+ compared with IEP- RT-DLBCL (6/20, 30% vs. 1/27, 3.7%; p = 0.0320). Two (2/36; 5.5%) cases were positive for EBER, both IEP+. There was no significant difference between the two groups in terms of age, sex, or time to transformation. Assessment of mismatch repair proteins demonstrated absence of microsatellite instability (MSI) in all cases (18/18; 100%). Notably, patients with brisk PD1+ TILs had a significantly better OS compared to those with a negative/low infiltrate (p = 0.0285).

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Authors and Affiliations

  1. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Siba El Hussein, L. Jeffrey Medeiros, Ellen Schlette, Hong Fang, Fatima Zahra Jelloul, Wei Wang, Rashmi Kanagal-Shamanna, Sanam Loghavi, Hong Yang, Shaoying Li, Jie Xu, Zhenya Tang, Beenu Thakral, Keyur Patel & Joseph D. Khoury

  2. Department of Pathology, The University of Rochester Medical Center, Rochester, NY, USA

    Siba El Hussein

  3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Stephen K. Gruschkus & Peng Wei

  4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Warren Fiskus, Nitin Jain, William G. Wierda & Kapil N. Bhalla

  5. Department of Pathology & Microbiology, The University of Nebraska Medical Center, Omaha, NE, USA

    Joseph D. Khoury

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  1. Siba El Hussein
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Contributions

Concept, study development, and manuscript original draft: SEH, JDK. Experimental studies, data analysis, and resources: LJM, SG, PW, ES, HF, FZJ, WW, WF, RKS, HY, SL, JX, ZT, BT, NJ, WW, KP, and KB. All authors contributed to the final version of the manuscript.

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Correspondence to Siba El Hussein or Joseph D. Khoury.

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Supplementary Information

Supplemental Table 1.

Details of the immunohistochemistry staining platform of the markers studied. RTU*: Ready to use by the vendor (DOCX 13 kb)

Supplemental Figure 1.

Overall Survival by immune evasion status defined as follows: Cases demonstrating high-positive expression (>50%) of PD1 and/or PD-L1 on neoplastic cells. 0: Negative, 1: Positive (JPG 48 kb)

Supplemental Figure 2.

Overall Survival by PD1 expression in neoplastic cells. 0 : Negative (expressed on <5% of neoplastic cells), 1: Low positive (expressed on 5-20% of neoplastic cells), 2: Positive (expressed on 20-50% of neoplastic cells), 3: High positive (expressed on >50% of neoplastic cells) (JPG 51 kb)

Supplemental Figure 3.

Overall Survival by PD-L1 expression in neoplastic cells. 0 : Negative, 1: Low positive (expressed on 5-20% of neoplastic cells), 2: Positive (expressed on 20-50% of neoplastic cells), 3: High positive (expressed on >50% of neoplastic cells) (JPG 56 kb)

Supplemental Figure 4.

Overall Survival by CD30 expression in neoplastic cells. 0: Negative, 1: Positive (JPG 49 kb)

Supplemental Figure 5

a-b. (a) Illustration of a case of Richter transformation-diffuse large B-cell lymphoma variant (RT-DLBCL) with (b) retained mismatch protein expression (MLH1/PMS2 and MSH2/MSH6) by immunohistochemistry (i.e. Microsatellite stable) (PNG 7485 kb)

High Resolution Image (TIF 1840 kb)

Supplemental Figure 5b

(PNG 9876 kb)

High Resolution Image (TIF 2136 kb)

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El Hussein, S., Medeiros, L.J., Gruschkus, S.K. et al. Immune evasion phenotype is common in Richter transformation diffuse large B-cell lymphoma variant. Virchows Arch 482, 1011–1019 (2023). https://doi.org/10.1007/s00428-023-03520-x

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