Abstract
Immunotherapies are rapidly being integrated into standard of care (SOC) therapy in conjunction with surgery, chemotherapy, and radiotherapy for many cancers and a large number of clinical studies continue to explore immunotherapy alone and as part of combination therapies in patients with cancer. It is evident that clinical effectiveness of immunotherapy is limited to a subset of patients and improving immunotherapy related outcomes remains a major scientific and clinical effort. Understanding the immune cell subset phenotype and activation/functional status (cellular immunome) prior to and post therapy is therefore critical to develop biomarkers that (1) will predict if a patient will respond to immunotherapy and (2) are a result of immunotherapy. In this study, we investigated local (tumor) and peripheral (blood) cellular immunome of patients with melanoma, breast cancer, and brain cancer using a rapid and reliable standardized, multiparameter flow cytometry assay. We used this approach to monitor changes in the peripheral cellular immunome in women with breast cancer undergoing SOC therapy. Our analysis is unique because it is conducted using matched fresh tumor tissue and blood from patients in real-time, within 2–3 h of sample acquisition, and provides insight into the innate and adaptive immune cell profile in blood and tumor. Specific to blood, this approach involves no manipulation and evaluates all immune subsets such as T cells, B cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), neutrophils, eosinophils, and basophils using 0.5 ml of blood. Analysis of the corresponding tumor provides much needed insight into the phenotype and activation status of immune cells, especially T and B cells, in the tumor microenvironment vs. the periphery. This analysis will be used to assess baseline and therapy-mediated changes in local and peripheral cellular immunome in patients with glioblastoma, breast cancer, and melanoma in planned immunotherapy clinical studies.
Highlights
Over the past 7 years, immunotherapy has dramatically changed the treatment landscape for many solid tumor and hematologic malignancies [1,2,3,4,5]
Basic phenotyping analysis revealed that brain tumor patients had 3-8-fold lower percentages of circulating lymphocytes compared to melanoma or breast cancer patients
The analysis presented in this manuscript was done using paired tumor and blood samples from patients with cancer with the following objectives: [1] examine blood and tumor cellular immunome in patients with cancer; [2] determine feasibility of this approach across different tumor types, and [3] assess if the experimental protocol is reproducible and precise to allow longitudinal monitoring of the peripheral cellular immunome to measure changes in response to therapies
Summary
Over the past 7 years, immunotherapy has dramatically changed the treatment landscape for many solid tumor and hematologic malignancies [1,2,3,4,5]. Immune checkpoint blockade with antibodies that block CTLA-4, PD-1 or PD-L1 have resulted in durable clinical responses in patients with advanced melanoma, lung, kidney, bladder, and colorectal cancer, but both primary and acquired resistance occur in the majority of patients [1,2,3,4,5, 11]. Several components of pre-existing anti-tumor immunity in patients have emerged as key regulators in determining sensitivity to checkpoint blockade [3, 12,13,14]. This suggests that the therapeutic efficacy of immunotherapies can be enhanced with novel combination therapies that promote immunological responses. Novel combination strategies can help overcome the resistance currently seen and may provide rationale for expansion of these same combination therapies to other solid tumors [15]
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