Quantification and Profiling of Early and Late Differentiation Stage T Cells in Mantle Cell Lymphoma Reveals Immunotherapeutic Targets in Subsets of Patients.

Simple Summary: In our study, we investigated immune regulation in a subtype of lymphoma called mantle cell lymphoma (MCL). Our goal was to understand how different types of immune cells, specifically T cells, behave in MCL. To do this, we combined image analysis and a technology called digital spatial profiling. We looked at tumor tissue from 102 MCL patients and analyzed different T-cell subsets. Interestingly, we found that late-stage differentiated T cells (CD57+) were more common in tumor-rich areas. These T cells also showed an increased expression of immune suppressive markers. We identified potential targets for treatment, such as CD47, IDO1, and CTLA-4. Additionally, we found that patients with sparse T-cell infiltration had an increased amount of GITR, which tentatively can be therapeutically targeted. Our findings shed light on previously unknown features of T-cell behavior in MCL. With the aim to advance the understanding of immune regulation in MCL and to identify targetable T-cell subsets, we set out to combine image analysis and spatial omic technology focused on both early and late differentiation stages of T cells. MCL patient tissue (n = 102) was explored using image analysis and GeoMx spatial omics profiling of 69 proteins and 1812 mRNAs. Tumor cells, T helper (TH) cells and cytotoxic (TC) cells of early (CD57−) and late (CD57+) differentiation stage were analyzed. An image analysis workflow was developed based on fine-tuned Cellpose models for cell segmentation and classification. TC and CD57+ subsets of T cells were enriched in tumor-rich compared to tumor-sparse regions. Tumor-sparse regions had a higher expression of several key immune suppressive proteins, tentatively controlling T-cell expansion in regions close to the tumor. We revealed that T cells in late differentiation stages (CD57+) are enriched among MCL infiltrating T cells and are predictive of an increased expression of immune suppressive markers. CD47, IDO1 and CTLA-4 were identified as potential targets for patients with T-cell-rich MCL TIME, while GITR might be a feasible target for MCL patients with sparse T-cell infiltration. In subgroups of patients with a high degree of CD57+ TC-cell infiltration, several immune checkpoint inhibitors, including TIGIT, PD-L1 and LAG3 were increased, emphasizing the immune-suppressive features of this highly differentiated T-cell subset not previously described in MCL. [ABSTRACT FROM AUTHOR]