Listeria-based vaccination against the pericyte antigen RGS5 elicits anti-vascular effects and colon cancer protection.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality despite efforts to improve standard interventions. As CRC patients can benefit from immunotherapeutic strategies that incite effector T cell action, cancer vaccines represent a safe and promising therapeutic approach to elicit protective and durable immune responses against components of the tumor microenvironment (TME). In this study, we investigate the pre-clinical potential of a Listeria monocytogenes (Lm)-based vaccine targeting the CRC-associated vasculature. CRC survival and progression are reliant on functioning blood vessels to effectively mediate various metabolic processes and oxygenate underlying tissues. We, therefore, advance the strategy of initiating immunity in syngeneic mouse models against the endogenous pericyte antigen RGS5, which is a critical mediator of pathological vascularization. Overall, Lm-based vaccination safely induced potent anti-tumor effects that consisted of recruiting functional Type-1-associated T cells into the TME and reducing tumor blood vessel content. This study underscores the promising clinical potential of targeting RGS5 against vascularized tumors like CRC.

Targeting the pericyte antigen DLK1 with an alpha type-1 polarized dendritic cell vaccine results in tumor vascular modulation and protection against colon cancer progression.

Despite the availability of various treatment options, colorectal cancer (CRC) remains a significant contributor to cancer-related mortality. Current standard-of-care interventions, including surgery, chemotherapy, and targeted agents like immune checkpoint blockade and anti-angiogenic therapies, have improved short-term patient outcomes depending on disease stage, but survival rates with metastasis remain low. A promising strategy to enhance the clinical experience with CRC involves the use of dendritic cell (DC) vaccines that incite immunity against tumor-derived blood vessels, which are necessary for CRC growth and progression. In this report, we target tumor-derived pericytes expressing DLK1 with a clinically-relevant alpha type-1 polarized DC vaccine (αDC1) in a syngeneic mouse model of colorectal cancer. Our pre-clinical data demonstrate the αDC1 vaccine's ability to induce anti-tumor effects by facilitating cytotoxic T lymphocyte activity and ablating the tumor vasculature. This work, overall, provides a foundation to further interrogate immune-mediated mechanisms of protection in order to help devise efficacious αDC1-based strategies for patients with CRC.

The Role of Complement in Angiogenesis.

The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy.

Complement as Prognostic Biomarker and Potential Therapeutic Target in Renal Cell Carcinoma.

Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.