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T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process that can increase frequencies of tumor-infiltrating lymphocytes through promoting the development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model that allows for coevolution of the tumor microenvironment and the immune response to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but also activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on the TNF receptor and independent of lymphotoxin β receptor–mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer. Cancer Immunol Res; 5(11); 1005–15. ©2017 AACR.

Colorectal cancer is second leading cause of cancer death. There have been many approaches proposed, such as anti-cancer drugs, chemotherapy and radiotherapy, however, there are still lack of breakthrough therapy designation. Cancer immunotherapies hold great promise, where the mechanism of interaction between immune cell and tumor remains poorly understood. Understanding of immune cell infiltration in solid tumor plays an important role in cancer immunotherapy. This paper describes injection molded plastic chip to mimic complex three-dimensional tumor-vasculature for evaluating immune cell infiltration and their cytotoxicity. Our device facilities simple and high-throughput screening, constituting of 28 wells per device. Using our system, Co-culture conditions that both tumors and blood vessels were adequately benefited were established. Also, we characterized the aberrant vasculature according to the colorectal tumor subtypes and confirmed increased blood vessel the permeability, which is the major feature of aberrant tumor vasculature. Moreover, we evaluated Natural killer(NK) cell infiltration and cytotoxicity according CMS subtypes. NK cell showed higher cytotoxicity to CMS 1 type colorectal cancer compared to the other subtypes. This result confirmed that NK cell is the crucial effector in innate immune system as a first line of defense against pathogens. Therefore, we propose our plastic microfluidic chip as a high-throughput screening platform to evaluate lymphocyte cytotoxicity to various solid tumor including immune infiltration. Citation Format: Jiyoung Song, Hyeri Choi, Dohyun Park, James Yu, Nooli Jeon. High-throughput vascularized tumor array for In-vitro natural killer cell cytotoxicity testing [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO040.

Recent studies demonstrate an unexpected connection between aberrant transcription of noncoding RNA in tumors and innate immune system activation in the tumor microenvironment. Such RNA is often of unknown function and may consist of typically silenced interspersed elements, satellite repeats, and endogenous retroviruses. For instance, satellite RNA from the pericentromere (particularly HSATII) is abundantly transcribed in several solid tumors - such as pancreatic ductal adenocarcinoma - yet it is virtually silent in normal tissue. The genomic DNA repetitive regions this RNA is transcribed from frequently expand during tumorigenesis. Using novel quantitative methods, we have shown that a set of such repetitive elements, abundantly expressed in tumors, display sequence patterns typically associated with viruses. We therefore predicted they are immunogenic, particularly HSATII. In a novel, theory-experiment collaboration between the laboratories of Professors Benjamin Greenbaum and Nina Bhardwaj, the most significant set of these RNA have been validated as immunostimulatory (HSATII and murine GSAT), capable of activating antigen presenting cells - HSATII stimulated production of IL-6, IL-12 and TNFalpha (Tanne, et al., PNAS, 2015). At the same time a set of recent papers has shown that ERV transcription may be a predictor of immunotherapy response in melanoma. Hence, it is critical to profile key immunostimulatory endogenous RNA in the tumor microenviroment, understand which immune pathways different sets of such RNA activate, and assess the link between the specific pathways activated, prognosis, and immunotherapy. We further profile the landscape of activation and expression for endogenous elements. We have currently demonstrated a key set of noncoding RNAs preferentially expressed in cancer cells have sequence features that are immunostimulatory in humans, and have characterized the range and breadth of the expression of such elements in several solid tumors. We present several new results on the topic and the potential consequences of the aberrant expression of endogenous RNA that mimic pathogen features in cancer. Citation Format: Alexander Solovyov, Antoine Tanne, Luciana Muniz, Simona Cocco, Remi Monasson, Arnold Levine, David T. Ting, Nina Bhardwaj, Benjamin Greenbaum. Quantifying the landscape of immunostimulatory tumoral RNA [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A087.