Genetic Mutations of Tim-3 Ligand and Exhausted Tim-3+ CD8+ T Cells and Survival in Diffuse Large B Cell Lymphoma

Abstract

Tim-3 is a promising target for antitumor immunotherapy. A number of clinical trials are evaluating the efficacy of anti-Tim-3 therapies as a single agent or combinations in solid tumors and haematologic malignancies. However, there remains a considerable lack of data on Tim-3 signalling, especially the genetic characteristics and immune microenvironment, in diffuse large B cell lymphoma (DLBCL). Herein, we identified three genetic mutations in galectin-9, a major ligand of Tim-3, in six patients with DLBCL (6/188, 3.2%) that were not detected in the COSMIC database. The Oncomine database showed that the mRNA levels of Tim-3 were higher in DLBCL cells than those in normal B cells. Multiplexed immunofluorescence revealed that patients with Tim-3-expressing tumor-infiltrating lymphocytes (Tim-3+ TILs) exhibited poor outcomes than those with Tim-3- TILs ( p = 0.041 ). The median survival times of these patients were 65.0 (95% confidence interval (CI): 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and found that patients with exhausted Tim-3+ CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) exhibited shorter survival than those with nonexhausted Tim-3- CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9; p = 0.034 ). Overall, these findings provide the genetic status of the Tim-3 ligand in DLBCL. Patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, thus highlighting the possibility of potential therapeutic applications of the inhibition of Tim-3 alone or in combination with other immune checkpoints for treatment of patients with DLBCL.

Multimodal and spatially resolved profiling identifies distinct patterns of T-cell infiltration in nodal B-cell lymphoma entities

“…Higher proportions of these cells were not significantly linked to cell-of-origin or genetic subtypes in DLBCL but instead associated with inferior survival in FL and DLBCL patients. These results are in line with previous studies that used TIM3 or LAG3 as surrogate markers to estimate Tcell exhaustion in DLBCL [51] or FL patients [52]. PD1 + TIM3 + T TOX cells were located within several spatial neighborhoods, thereby allowing for contact with various types of immune cells.…”

Comprehensive Analysis of the Prognosis and Correlations with Immune Infiltration of CXC Chemokine Family Members in Diffuse Large B-cell Lymphoma

“…In recent years, the suppression therapy of immune checkpoints has become a breakthrough point for refractory/relapsed malignant tumors. Some scholars have found that the combined inhibition of PD1/PD-L1, PD1/CTLA4, PD1/TIM-3, and PD1/LAG3 can significantly inhibit cytokines in response to malignant neoplasm therapy [5,[41][42][43][44]. T cell immunoglobulin and ITIM domain (TIGIT), as an inhibitory receptor, is an emerging cancer immunotherapy target.…”

Engaging the Innate and Adaptive Antitumor Immune Response in Lymphoma

“…The cognate ligand of TIM-3, Gal-9, is expressed by some lymphoma cells and MDSCs, where it serves to drive Th1 cell death and CTL immune exhaustion and, thus, impair antitumor T-cell responses [ 117 ]. Indeed, TIM-3 overexpression and exhaustion of TIM-3+ TILs have been shown to correlate with inferior outcomes in DLBCL [ 34 , 118 ]. The precise mechanisms by which TIM-3 expression on innate immune cells (i.e., NK cells, macrophages, and dendritic cells) contributes to immune dysfunction remain to be elucidated [ 116 ].…”

“…Moreover, TIM-3 and LAG-3 are nearly always expressed in the TME of cHL (>96% of cases) [ 213 ]. In both DLBCL and FL, expression of these ligands on TILs has been correlated with a decrease in treatment efficacy and overall survival [ 34 , 118 , 212 , 214 ]. Preclinical studies have shown enhanced cytotoxic and antitumor T-cell responses in the presence of anti-TIM-3 and anti-LAG-3 antibodies [ 34 , 215 ].…”