Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

Abstract

Advances in immunotherapy have achieved remarkable clinical outcomes in tumors with low curability, but their effects are limited, and increasing evidence has implicated tumoral and non-tumoral components of the tumor microenvironment as critical mediators of cancer progression. At the same time, the clinical successes achieved with minimally invasive and optically-guided surgery and image-guided and ablative radiation strategies have been successfully implemented in clinical care. More effective, localized and safer treatments have fueled strong research interest in radioimmunotherapy, which has shown the potential immunomodulatory effects of ionizing radiation. However, increasingly more observations suggest that immunosuppressive changes, metabolic remodeling, and angiogenic responses in the local tumor microenvironment play a central role in tumor recurrence. In this review, we address challenges to identify responders vs. non-responders to the immune checkpoint blockade, discuss recent developments in combinations of immunotherapy and radiotherapy for clinical evaluation, and consider the clinical impact of immunosuppressive changes in the tumor microenvironment in the context of surgery and radiation. Since the therapy-induced modulation of the tumor microenvironment presents a multiplicity of forms, we propose that overcoming microenvironment related resistance can become clinically relevant and represents a novel strategy to optimize treatment immunogenicity and improve patient outcome.

Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy

“…RT is a well-known immune modulator that can provide danger signals to awaken the immune system [ 19 , 21 , 22 ]. Numerous preclinical cancer models including our research in brain and prostate tumor models have shown that RT can change the TME [ 22 , 28 , 32 , 33 , 34 , 35 , 36 , 37 ] and provoke anti-tumor immune responses locally and systemically [ 26 , 28 , 38 , 39 , 40 ].…”

“…Radiotherapy (RT) is an immune modulator [ 19 , 20 , 21 , 22 ]. Clinical cases showed the addition of RT to anti-CTLA-4 treatment significantly prolonged the survival of advanced melanoma.…”

Vitamin D: Possible Therapeutic Roles in Hepatocellular Carcinoma

“…Tumor growth, invasion, and metastasis are generally affected by the interactions between the tumors and their respective microenvironments (87). Understanding these bidirectional interactions between the tumor cells and the environment could open up therapeutic targets and regimes in liver cancer treatment (88)(89)(90). Although VD influences angiogenesis, metastasis, and cancer progression in TME, the active form of VD, 1, 25 (OH) 2 D 3 modulates a couple of stroma cells explicitly, suppresses tumor growth, and act as an anti-inflammatory agent within the TME, leading to cancer reduction (91).…”

Metabolic Classification and Intervention Opportunities for Tumor Energy Dysfunction

“…Once lymphocytes have been activated, they begin a metabolic transition from oxidative phosphorylation to aerobic glycolysis. Immune and tumor cells compete within the tumor microenvironment, and increased nutrient consumption by tumor cells achieves an immunosuppressive microenvironment by hindering T cell metabolism [ 151 ]; hence, interest in targeting both tumor and T cell metabolism exists, which can enhance immunity and improve the success of immunotherapies [ 152 ].…”

“…Glucose is a critical substrate for effector T cells and M1 macrophages, which both require aerobic glycolysis for their activation and full antitumor effector functions. Immunometabolism is therefore highlighted as a promising field in energy dysfunction treatment and tumor macroenvironment reprogramming [ 151 ]. Remarkably, immunotherapy action interconnects metabolic and immune regulation, diet [ 154 ], physical exercise, sleep, microbiota [ 155 ], and age [ 156 ], making these fundamentals of the macroenvironment a vital companion in comprehensive treatment of tumor energetic dysfunction.…”