Abstract
A systemic analysis of the tumor-immune interactions within the heterogeneous tumor microenvironment is of particular importance for understanding the antitumor immune response. We used multiplexed immunofluorescence to elucidate cellular spatial interactions and T-cell infiltrations in metastatic melanoma tumor microenvironment. We developed two novel computational approaches that enable infiltration clustering and single cell analysis—cell aggregate algorithm and cell neighborhood analysis algorithm—to reveal and to compare the spatial distribution of various immune cells relative to tumor cell in sub-anatomic tumor microenvironment areas. We showed that the heterogeneous tumor human leukocyte antigen-1 expressions differently affect the magnitude of cytotoxic T-cell infiltration and the distributions of CD20+ B cells and CD4+FOXP3+ regulatory T cells within and outside of T-cell infiltrated tumor areas. In a cohort of 166 stage III melanoma samples, high tumor human leukocyte antigen-1 expression is required but not sufficient for high T-cell infiltration, with significantly improved overall survival. Our results demonstrate that tumor cells with heterogeneous properties are associated with differential but predictable distributions of immune cells within heterogeneous tumor microenvironment with various biological features and impacts on clinical outcomes. It establishes tools necessary for systematic analysis of the tumor microenvironment, allowing the elucidation of the “homogeneous patterns” within the heterogeneous tumor microenvironment.
Highlights
The success of cancer immune checkpoint therapies depends on their ability to mobilize immune cells and direct their activities into the highly heterogeneous tumor microenvironment (TME), where they exert their antitumor effects
To examine the heterogeneity of tumor cells in metastatic melanoma (MM) tissues, we examined the tumor HLA-1 expression levels between MM samples obtained from different patients
tumor microarray (TMA) only randomly reflects part of the entire heterogeneous TME, this result directly confirms the interpatient heterogeneity of melanoma HLA-1 expression in a larger sample size
Summary
The success of cancer immune checkpoint therapies depends on their ability to mobilize immune cells and direct their activities into the highly heterogeneous tumor microenvironment (TME), where they exert their antitumor effects. Most cancer immunotherapy efforts, including immune checkpoint inhibitors (e.g., anti–programmed cell death protein 1 [PD1] antibodies), are aimed at maximizing the effect of tumor-infiltrating lymphocytes (TILs) through different approaches [2,3,4,5]. The TME is a heterogeneous mixture of various immune and tumor cells with different functional phenotypes and spatial distribution patterns. The outcome of dynamic interactions between cells with different functional profiles within micro-anatomic locations of TME will determine the success of immune destruction of tumors, collectively determining the outcome of immunotherapy. Understanding the functional and spatial interplays between tumor and different immune populations will likely provide insight to the variable treatment responses and to improve outcomes of cancer immunotherapy. Due to the complexity of the TME heterogeneity, tools for systematic analysis of the micro-anatomic in situ cellular level interplay are currently lacking
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
