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.
Highlights
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments
We interrogate the spatial organization of the CTCL microenvironment in the same cohort of patients enrolled in the previously published pembrolizumab clinical trial, which failed to identify a predictive biomarker of response
The SpatialScore was lower in responders pretreatment when calculated with PD-1+ CD4+ T cells versus all CD4+ T cells, implying increased effector activity in this T cell subset. These results suggest that PD-1+ CD4+ T cells are primed for increased antitumor activity in responders, which is enhanced in the immune-activated tumor microenvironment (TME) that develops following pembrolizumab therapy
Summary
Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. A recent Cancer Immunotherapy Trials Network (CITN) multicenter phase II clinical trial (NCT02243579) of the anti-PD1 immunotherapy, pembrolizumab, in advanced cutaneous T cell lymphoma (CTCL) showed that 38% of patients achieved a sustained clinical response, whereas 25% experienced disease progression[13] Despite these outcome discrepancies, biomarker studies with traditional immunohistochemistry (IHC), gene expression profiling, and mass cytometry did not predict pembrolizumab response[13]. Recent studies show that immune cells are not randomly distributed within the TME, but rather purposefully organized into cellular neighborhoods and niches that facilitate anti- or pro-tumor functions[14,15] This raises the question of how PD-1 blockade alters spatial cellular context, and in turn, whether such changes can predict clinical response to pembrolizumab therapy in CTCL. We interrogate the spatial organization of the CTCL microenvironment in the same cohort of patients enrolled in the previously published pembrolizumab clinical trial, which failed to identify a predictive biomarker of response
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