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Suppressive myeloid populations in the tumor microenvironment are associated with worse survival of cancer patients and low effectiveness of T cell checkpoint inhibitors. Recently, several early clinical studies have produced positive data for therapies aimed at repolarizing suppressive myeloid populations in the tumor microenvironment. One new macrophage repolarizing target, PSGL-1, is expressed at high levels on immuno-suppressive TAMs and differentiated M2 macrophages. PSGL-1 has been shown to have an immune-modulatory activity, which includes its role in maintaining a suppressive functional macrophage state. To assess the ability of PSGL-1 antibodies to convert macrophages and the tumor microenvironment from an immuno-suppressive toward a pro-inflammatory state, we employed in vitro primary macrophage and multi-cellular assays, ex vivo patient-derived tumor cultures, and a humanized mouse PDX model. We have determined that our lead anti-PSGL-1 antibody repolarized M2-like macrophages to a more M1-like state both phenotypically and functionally as assessed in primary in vitro macrophage assays. Transcriptomics profiling of M2c macrophages showed that the anti-PSGL-1 antibody upregulated TNF-a/NF-kB and chemokine-mediated signaling, while downregulating oxidative phosphorylation, fatty acid metabolism and Myc signaling pathways, consistent with a broad M2-to-M1 shift of the macrophage state. Furthermore, these repolarized M1-like macrophages enhanced the inflammatory response in complex multi-cellular assays. The PSGL-1 antibody also showed efficacy in a humanized mouse PDX model of melanoma. The antibody suppressed tumor growth to a significantly greater degree compared to anti-PD-1. At the cellular and molecular levels, the anti-PSGL-1 treatment led to a more enhanced inflammatory microenvironment, including a reduced M2:M1 macrophage ratio, and an increase in systemic pro-inflammatory mediators. Compared to anti-PD-1 monotherapy, anti-PSGL-1 alone and in combination with anti-PD-1 increased the fraction of effector CD8+ T cells among the infiltrating T cells. Significant combination effects of anti-PSGL-1 plus anti-PD-1 were seen at the cellular and molecular levels within the tumor tissue, the spleen, and peripheral blood. Lastly, pre-clinical efficacy of our lead anti-PSGL-1 antibody was demonstrated using ex vivo cultures of fresh patient-derived tumors that preserve the cellular heterogeneity of the TME. Anti-PSGL-1 increased production of inflammatory cytokines and chemokines involved in immune activation of the TME and T cell recruitment. The data presented here provide biological and mechanistic support for clinical testing of antibodies targeting PSGL-1 for the treatment of cancer. Citation Format: Ani Nguyen, Jessica Ritter, Mohammad Zafari, Denise Manfra, Veronica Komoroski, Brian O'Nuallain, Ryan Phennicie, Kevin Kauffman, Dominika Nowakowska, Joe Wahle, Steve Sazinsky, Michael Brehm, Igor Feldman, Tatiana Novobrantseva. PSGL-1 blocking antibodies repolarize tumor associated macrophages, reduce suppressive myeloid populations and induce inflammation in the tumor microenvironment, leading to suppression of tumor growth [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P107.

Objective: Verrucae plantaris (VP) results from environmental exposure to human papillomavirus causing plantar warts of the foot, resistantto treatment, and high recurrence rates. Current treatment paradigms focus on the treatment of lesions as opposed to primary prophylaxis. Wehypothesize that a topical combination of herbal supplement with anti-viral properties and a vitamin derivative* can be used prophylactically todecrease the primary incidence.Methods: We initiated a double-blinded clinical study with participants (n=282) randomization into control (lotion emollient only) (n=120),treatment (herbal and vitamin derivative) (n=110) and no treatment (NT) (n=52). Participants underwent examination of the feet at baseline (0months) to exclude VP lesions and were randomized to receive a bottle containing topical lotion with emollient only, control (C), lotion with an herbaland vitamin derivative, treatment (T), or NT, where participants did not apply anything to their feet. C and T participants applied lotion topically to thefeet once daily and were examined at 3, 6, 9, and 12 months to document the incidence of VP.Results: No incidence of VP occurred in the T group (0/110=0% incidence), two lesions in the C group (2/120=1.7% incidence), and five lesions inthe NT group (5/52=9.6% incidence).Conclusion: Treatments for VP rely on treating lesions after they occur, have high degrees of variability in success, risk of continued transmissionduring treatment, and have high rates of recurrence. Although the study number is relatively low, early indications show decreasing incidence ofVP from 9.6% in participants with NT to 1.7% in participants who used lotion only, suggesting increased health of the plantar epidermis, and 0%incidence in those participants applying topical herbal and vitamin derivative*. Additional study with increased numbers of participants is warranted.

Cancer affects one in three people worldwide. Surgery remains the primary curative option for localized cancers, but good prognoses require complete removal of primary tumors and timely recognition of metastases. To expand surgical capabilities and enhance patient outcomes, we developed a six-channel color/near-infrared image sensor inspired by the mantis shrimp visual system that enabled near-infrared fluorescence image guidance during surgery. The mantis shrimp's unique eye, which maximizes the number of photons contributing to and the amount of information contained in each glimpse of its surroundings, is recapitulated in our single-chip imaging system that integrates arrays of vertically stacked silicon photodetectors and pixelated spectral filters. To provide information about tumor location unavailable from a single instrument, we tuned three color channels to permit an intuitive perspective of the surgical procedure and three near-infrared channels to permit multifunctional imaging of optical probes highlighting cancerous tissue. In nude athymic mice bearing human prostate tumors, our image sensor enabled simultaneous detection of two tumor-targeted fluorophores, distinguishing diseased from healthy tissue in an estimated 92% of cases. It also permitted extraction of near-infrared structured illumination enabling the mapping of the three-dimensional topography of tumors and surgical sites to within 1.2-mm error. In the operating room, during surgical resection in 18 patients with breast cancer, our image sensor further enabled sentinel lymph node mapping using clinically approved near-infrared fluorophores. The flexibility and performance afforded by this simple and compact architecture highlights the benefits of biologically inspired sensors in image-guided surgery.

We have designed, fabricated, and tested a hexachromatic imager for near-infrared fluorescence image-guided surgery capable of simultaneously imaging three visible and near-infrared spectral channels. The sensor is comprised of 1280 by 720 pixels yielding a 48 dB signal-to-noise-ratio and achieving a minimum indocyanine green concentration detectability of 5 nM. The imaging sensor combines the vertically stacked photodiode technology and an array of pixelated spectral interference filters in a single-chip single-snapshot architecture yielding high sensitivity and clinical translation.

We have designed, fabricated, and tested a hexachromatic imager for near-infrared fluorescence image-guided surgery capable of simultaneously imaging three visible and near-infrared spectral channels. The sensor is comprised of 1280 by 720 pixels yielding a 48 dB signal-to-noise-ratio and achieving a minimum indocyanine green concentration detectability of 5 nM. The imaging sensor combines the vertically stacked photodiode technology and an array of pixelated spectral interference filters in a single-chip single-snapshot architecture yielding high sensitivity and clinical translation.

Image-guided surgery (IGS) can improve the patient’s outcome by providing meaningful real-time information about the location of cancerous tumors and surrounding tissue, aiding in the elimination of positive tumor margins and reducing iatrogenic damage. However, the clinical need for imaging systems that can provide real-time feedback under real operating room settings remains unmet. State-of-the-art imaging systems for near-infrared fluorescence IGS rely on a series of complex optics and several imaging sensors. As a result, these systems are bulky and expensive, and their architecture lacks the versatility to simultaneously image multiple fluorophores, effectively making them cumbersome when merged into the current surgical workflow. To address these shortcomings, we have designed a multi-spectral imager capable of spatially co-registered hexachromatic vision: three spectral channels in the visible spectrum for the identification of anatomical features in color and three spectral channels in the near-infrared spectrum for the simultaneous identification of multiple near-infrared fluorescence dyes used in IGS. Our single-chip imaging sensor combines the vertically stacked photodetectors technology with pixelated interference filters to create a multi-spectral imager that can help surgeons make clinically relevant decisions in real time, with an effective resolution of 1280x720x3 photodiodes and a frame rate of 24 FPS. Our imager has the ability to identify different shades of near-infrared fluorescent light, allowing the surgeon to use and differentiate multiple fluorophores as molecular probes with high sensitivity. Pre-clinical data is shown where simultaneous imaging of anatomical features in color, and identification of nerves and cancerous tumors, are achieved using multiple near-infrared fluorescent agents.

We have created a six-channel multispectral imager for the simultaneous space- and time-detection of color and multiple near-infrared fluorescent molecular markers by integrating the vertically stacked photodetector technology with pixelated spectral interference filters.