Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

Abstract

Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.

Editorial: Defining the Spatial Organization of Immune Responses to Cancer and Viruses In Situ

“…utilized multiplexed immunohistochemistry and image cytometry-based quantification to reveal co-localization of PD-1 + helper T cells and CD163 + TAMs within tumor cells nests as a negative prognostic indicator in HNSCC. This finding suggests that CD163 + TAMs exert their immunosuppressive effects on effector PD-1 + helper T cells, in line with recent orthogonal work showing that co-localization of PD-1 + CD4 + T cells and Tregs was associated with poor response to immunotherapy ( 18 ). Collectively, these studies provide a framework for utilizing advanced spatial analyses to interrogate the complexity of the tumor microenvironment and decode the therapeutic response in situ .…”

Rhesus Macaque CODEX Multiplexed Immunohistochemistry Panel for Studying Immune Responses During Ebola Infection

“…The initial host antibody marker selection was based on prior knowledge and antibody clones described in previous studies (12)(13)(14)(15)(16)(17)(18)(19). Various factors, such as the time between tissue collection and fixation, duration of fixation, processing into paraffin blocks, and storage conditions can affect tissue integrity and immunohistochemical analysis (20).…”

Multicellular modules as clinical diagnostic and therapeutic targets

“…Thus, how does one address understanding how given arrangements of cells represent tissue function at the local and global scale? Multiplexed tissue imaging is advancing our understanding of spatial context in areas such as oncology [5][6][7][8][9][10][11][12], immunology [13,14], and microbiology [15,16]. An early focus of the field has been the tumor immune microenvironment and its implications for immunotherapy.…”