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Immune evasion phenotype is common in Richter transformation diffuse large B-cell lymphoma variant
Siba El Hussein1,2, L Jeffrey Medeiros3, Stephen K Gruschkus4
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. elhusseinsiba@gmail.com.
Insights
Immune checkpoint inhibitors show promise for Richter transformation-diffuse large B-cell lymphoma (RT-DLBCL). High PD-1/PD-L1 expression (immune evasion phenotype) and brisk PD1+ tumor-infiltrating lymphocytes correlate with better outcomes.
Area of Science:
- Oncology
- Immunology
- Pathology
Background:
- Richter transformation-diffuse large B-cell lymphoma (RT-DLBCL) is an aggressive variant with limited therapeutic options.
- Immune checkpoint inhibitors, specifically PD-1 inhibitors, have emerged as a potential treatment strategy for RT-DLBCL.
Purpose of the Study:
- To investigate the expression of PD-1, PD-L1, CD30, and microsatellite instability (MSI) in RT-DLBCL.
- To define an 'immune evasion phenotype' (IEP) based on PD-1/PD-L1 expression and assess its correlation with other markers and clinical outcomes.
- To evaluate the prognostic significance of PD1-positive tumor-infiltrating lymphocytes (TILs) in RT-DLBCL.
Main Methods:
- Sixty-four patients with RT-DLBCL were analyzed.
- Immunohistochemistry was used to assess PD-1, PD-L1, CD30, and MSI status (hMLH1, hMSH2, hMSH6, PMS1).
- Epstein-Barr virus-encoded RNA (EBER) was evaluated using in situ hybridization.
- PD-1 and PD-L1 expression on tumor cells were categorized as negative, low-positive, or high-positive.
- An immune evasion phenotype (IEP) was defined as high-positive PD-1 and/or PD-L1 expression.
- PD1-positive TILs were categorized as negative/low or brisk (>20%).
Main Results:
- 43.7% of patients (28/64) exhibited an IEP+ RT-DLBCL.
- Brisk PD1+ TILs were significantly more common in IEP+ tumors (60.7%) compared to IEP- tumors (14.7%; p = 0.001).
- CD30 expression was also significantly more frequent in IEP+ RT-DLBCL (30% vs. 3.7%; p = 0.0320).
- Two cases (5.5%) were EBER-positive, both within the IEP+ group.
- No significant differences in age, sex, or time to transformation were observed between IEP+ and IEP- groups.
- All cases showed absence of MSI (100%).
- Patients with brisk PD1+ TILs demonstrated significantly better overall survival (OS) compared to those with negative/low TILs (p = 0.0285).
Conclusions:
- The immune evasion phenotype (IEP) is prevalent in RT-DLBCL and is associated with increased PD1+ TILs and CD30 expression.
- Brisk PD1+ TILs are a significant positive prognostic factor for overall survival in RT-DLBCL patients.
- These findings support the investigation of immune checkpoint inhibitors in RT-DLBCL, particularly in patients with an IEP and brisk TIL infiltration.
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).
