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.
Highlights
Cancer treatment modalities vary considerably depending on stage and location, surgical excision and radiation therapy are an integral part of treatment for most solid tumors
In an era of exceptionally dynamic evolution of knowledge, some recently published clinical studies have reshaped the role of surgery such as neoadjuvant immunotherapy combinations leading to less invasive surgery for advanced melanoma, antiangiogenics as an alternative to immediate surgery in renal cell carcinoma or upfront treatments making surgery possible for more patients with pancreatic cancer [1]
Another interesting feature is that programmed death-1 (PD-1) blockade can induce clonal replacement preferentially of exhausted CD8+ T cells, meaning that T cells present at baseline may show reduced proliferation and that the response to immune checkpoint blockade (ICB) could be due to T cell clones that enter the tumor during the course of treatment [22]
Summary
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. 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
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