The complex immunosuppressive nature of solid tumor microenvironments poses a significant challenge to generating efficacious and durable anticancer responses. Photoimmunotherapy is a cancer treatment strategy by which an antibody is conjugated with a non-toxic light-activatable dye. Following administration of the conjugate and binding to the target tumor, subsequent local laser illumination activates the dye, resulting in highly specific target cell membrane disruption. Here we demonstrate that photoimmunotherapy treatment elicited tumor necrosis, thus inducing immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs). Photoimmunotherapy-killed tumor cells activated dendritic cells (DC), leading to the production of proinflammatory cytokines, T cell stimulation, priming antigen-specific T cells, and durable memory T cell responses, which led complete responder mice to effectively reject new tumors upon rechallenge. PD-1 blockade in combination with photoimmunotherapy enhanced overall anticancer efficacy, including against anti-PD-1-resistant tumors. The combination treatment also elicited abscopal anticancer activity, as observed by reduction of distal, non-illuminated tumors, further demonstrating the ability of photoimmunotherapy to harness local and peripheral T cell responses. With this work we therefore delineate the immune mechanisms of action for photoimmunotherapy and demonstrate the potential for cancer-targeted photoimmunotherapy to be combined with other immunotherapy approaches for augmented, durable anticancer efficacy. Moreover, we demonstrate responses utilizing various immunocompetent mouse models, as well as in vitro data from human cells, suggesting broad translational potential.

INTRODUCTION: Cancer cell-targeted photoimmunotherapy (PIT) is a platform technology under development for the treatment of various cancers. PIT is a drug + device combination that utilizes monoclonal antibodies conjugated to a dye (IRDye 700DX) that are activated with nonthermal red light illumination to induce rapid cell death by necrosis. Binding of the antibody-dye conjugate to cancer cells followed by photoactivation with nonthermal red light elicits rapid necrosis of the cancer cells bound to the antibody conjugate, providing very high cancer cell specificity. Given the rapid cell necrosis induced by PIT treatment, we hypothesized that PIT also induces immunogenic cell death (ICD) as a step to activate immune cells in the tumor microenvironment. The objective of this study was to evaluate, through in vitro and in vivo experiments, whether PIT results in ICD of targeted cancer cells and activation of the innate and adaptive immune response. METHODS: Human cancer cells (A431 and FaDu cells) were targeted by PIT, and evaluated for ICD markers in vitro. Human dendritic cells exposed to supernatants of PIT-killed cancer cells were evaluated for activation markers and cytokine production. An immunocompetent mouse model for PIT was also developed to determine intratumoral immune activation after treatment with PIT. RESULTS: After photoactivation, PIT-targeted human cancer cells upregulated cell surface ICD markers Hsp70, Hsp90, and calreticulin, as well as release of intracellular HMGB1. Human dendritic cells exposed to PIT-killed cell supernatants exhibited markers of immune activation (CD86 and MHCII), and secreted proinflammatory cytokines including TNF, IP-10, IL-1β, MIP-1a, MIP-1b, and IL-8. In an immunocompetent mouse model, tumors treated by PIT displayed increased percentage of intratumoral CD11c+ dendritic cells with activation markers MHCIIhigh, CD80, and PD-L1. In addition, intratumoral natural killer cells from PIT treated tumors displayed increased cytotoxic activity (CD3-DX5+CD69+ and CD3-DX5+CD107a+), as well as an increased population of total CD3+ CD8+ T cells, compared to non-PIT treated tumors. CONCLUSION: Cancer cells killed by PIT undergo ICD, which results in the activation of intratumoral innate and adaptive immune response in a preclinical mouse model. Combination studies with PIT and immune modulators are warranted to explore potential synergistic anticancer effects. Citation Format: Michelle A. Hsu, Stephanie M. Okamura, Daniele M. Bergeron, Deepak Yadav, Jerry J. Fong, Roger Heim, Miguel Garcia-Guzman. Cancer cell-targeted photoimmunotherapy elicits immunogenic cell death and activates the innate and adaptive immune response in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3734.

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Women with increased risk of the female athlete triad (Triad) are more susceptible to osteoporosis compared to other women. The study included 65 women with increased risk of the Triad who had their osteoporosis health beliefs measured to assess their concern for the disease. Participants were female collegiate cross-country runners at different levels of competition, including National Association of Intercollegiate Athletics (NAIA) and National Collegiate Athletic Association (NCAA) Divisions III, II, and I. Although these participants have an increased risk of the Triad and are more susceptible to osteoporosis, on a scale of 1 to 5, results showed that they had low to moderate perceived susceptibility to osteoporosis with a mean score as high as 2.81 and moderate perceived severity of osteoporosis with a mean score as high as 3.38. A statistically significant difference in perceived susceptibility to osteoporosis was found between female collegiate cross-country runners in the NAIA and those in the NCAA DIII. Reasons that could explain relatively low levels of concern for osteoporosis in female collegiate cross-country runners and reasons for significant differences in perceived susceptibility to osteoporosis are given, and recommendations for health education and intervention to help care for this population are provided.