A WIDE T‐CELL EXHAUSTION PATTERN IS FREQUENTIN THE TUMOR MICROENVIRONMENT OF RELAPSED/REFRACTORY B‐CELL LYMPHOMA PATIENTS AND COULD BE CIRCUMVENTED BY PDL1 BLOCKADE (2021)

Background: Relapsed/refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHL) remain incurable diseases and need novel therapeutic approaches. In the LYSA trial GATA (NCT03276468), 58 DLBCL and 58 FL R/R patients were treated by obinutuzumab (OBI) combined with BCL-2 inhibitor venetoclax (VEN) and anti-PDL1 atezolizumab (ATE) in order to test the synergy of chemo-free tumor-targeted therapies. The goal of the present study was to evaluate the influence of tumor microenvironment (TME) on the efficiency of this novel drug combination. Methods: A centralized pathological review was mandatory for all enrolled cases. As a result, 67 cases including 35 DLBCL (16 GC and 19 non-GC subtypes) and 32 FL (grade 1-2) with sufficient relapse material were selected for evaluating TME composition and immune checkpoints (ICP) expression using standard and/or multiplexed IHC analyses. All stainings have been scored manually, and when possible validated using a computer-assisted software. Biopsy samples at diagnosis were also analyzed in 60% of cases. Non-parametric tests were used to test correlations between TME parameters and clinical responses assessed by Lugano criteria at the end of induction (EOI) after 8 cycles of ATE, OBI and VEN. Results: R/R FL exhibited a higher amount of CD3+ T-cells, CD4+ T-cells and CTL than R/R DLBCL (p < 0.001, p = 0.03 and p < 0.001). By contrast, R/R DLBCL contained more CD163+ macrophages than R/R FL (p = 0.029). TIM3 expression was higher in R/R DLBLC vs R/R FL (p = 0.036), whereas PD1 expression was higher in R/R FL than R/R DLCDL (p = 0.008). ICP expression and ME composition did not significantly vary between GC and non-CG DLBCL subtypes. As compared to the initial diagnosis, expressions of TIM3 in FL and TIGIT in DLBCL had a tendency to be increased at relapse, but no difference in terms of immune cell composition was observed. PD1/PDL1 expression was not correlated with clinical response, whereas higher expression of TIM3 and TIGIT (>15%) was associated with better response in R/R FL (50% versus 33% of CR) and R/R DLBCL (40% versus 0% of CR), respectively. Conclusions: We show herein that TME composition and ICP expression are distinct between R/R FL and R/R DLBCL and remain mostly unchanged after R-chemotherapy compared to initial biopsies, except for higher TIM3 and TIGIT expression levels. This preliminary study indicates that high expression of TIGIT in R/R DLBCL and TIM3 in R/R FL patients are correlated with responsiveness following OBI-VEN-ATE therapy. Thus, TIGIT and TIM3 expression could predict the efficacy of PD1/PD-L1 blockade in these settings. Overall, these data may reflect the triggering of a global T-cell exhaustion program in R/R B-NHLs, which can be at least in part circumvented by anti-PDL1 therapy. In future trials, targeting TIM3 and TIGIT might be considered as a synergistic strategy to enhance the benefit of PD1/PDL1 blockade in these patients. Keywords: Diagnostic and Prognostic Biomarkers No conflicts of interests pertinent to the abstract.