MRI of tumor-infiltrating lymphocytes using MRI-cytometry

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PROJECT SUMMARY This proposal seeks to further develop and validate a cell-size-based MR imaging method dubbed MRI-cytometry as a novel approach for imaging tumor-infiltrating lymphocytes (TILs), and to evaluate its potential as a surrogate imaging biomarker to predict treatment response to immune-checkpoint blockade (ICB) immunotherapy. ICB is the most widespread class of immunotherapies but it poses a new challenge to assess tumor therapeutic response. ICB induces infiltrations of TILs into tumors to kill cancer, but such increased numbers of TILs may lead to transient tumor enlargement, which is the current indicator of tumor progression i.e., non-responders. Therefore, effective response to ICB could be misdiagnosed as tumor progression i.e., pseudo-progression. There is often a much longer waiting period than conventional treatments to verify the persistence of tumor volume changes, which prevents timely adjustments of treatment plans particularly in non-responder patients, causing unwanted treatment delays, costs, and risks of toxicity. Current mainstream imaging methods require exogenous agents for labeling TILs, which significantly increases cost and risks of toxicity. To overcome these limitations, this application proposes a novel, exogenous-agent-free approach for imaging TILs. Because lymphocytes (5-10 μm in diameter with and without activation) are significantly smaller than most cancer cells (10-20 µm), cell size could be used as an endogenous contrast to distinguish “small” TILs from “large” cancer cells. The significantly increased TILs are expected to cause some unique microstructural changes e.g., decreased mean cell sizes and increased cell fractions of “small” cells. To detect these changes, we recently developed a cell-size-based MRI method dubbed MRI-cytometry for imaging cell size distribution and intracellular volume fractions in vivo. Based on our preliminary data, we hypothesize that MRI-cytometry can serve as a specific imaging biomarker of TILs, and hence can predict treatment response to ICB immunotherapy. To test our hypothesis, we propose three specific aims: Aim 1 [development]: To further develop MRI-cytometry imaging to overcome potentially confounding effects for accurate estimation of microstructural parameters. Aim 2 [validation]: To validate MRI-cytometry imaging to characterize lymphocyte infiltration following ICB immunotherapy using preclinical animal models. Aim 3 [evaluation]: To evaluate MRI-cytometry to predict tumor response to combinations of ICB immunotherapy and radiotherapy. Successful completion of this project will establish a new exogenous-agent-free MRI tool for imaging tumor-infiltrating lymphocytes following immune-checkpoint blockade immunotherapy. It can be used as an “add-on” to clinical MRI to reduce cost and risks of toxicity compared with those lymphocyte labeling methods. Moreover, the proposed approach is expected to be translated to the clinic easily, allowing clinicians to stratify responder and non-responder patients early to adjust treatment plans in the manner of personalized medicine.