Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract
Purpose
Radiofrequency ablation (RFA) has been shown to elicit tumor-specific T cell immune responses but is not sufficient to prevent cancer progression. Here we investigated immune suppressive mechanisms limiting the efficacy of RFA.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780056/

Experimental design
We performed a retrospective case-controlled study on patients with synchronous colorectal cancer liver metastases who had received primary tumor resection with or without pre-operative RFA for liver metastases. Tumor infiltrating T cells and tumoral PD-L1 expression in human colorectal cancer tissues were analyzed by immunohistochemistry. T cell immune responses and PD-1/PD-L1 expression were also characterized in a RFA mouse model. In addition, the combined effect of RAF and PD-1 blockade was evaluated in the mouse RFA model.

“Results
We found that RFA treatment of liver metastases increased not only T cell infiltration but also PD-L1 expression in primary human colorectal tumors. Using mouse tumor models, we demonstrated that RFA treatment of one tumor initially enhanced a strong T cell-mediated immune response in tumor. Nevertheless, tumor quickly overcame the immune responses by inhibiting the function of CD8+ and CD4+T cells, driving a shift to higher Treg to Teff ratio, and up-regulating of PD-L1/PD-1 expression. Furthermore, we established that the combined therapy of RFA and anti-PD-1 antibodies significantly enhanced T cell immune responses, resulting in stronger antitumor immunity and prolonged survival”

Conclusions
The PD-L1/PD-1 axis plays a critical role in dampening RFA-induced antitumor immune responses. And this study provides a strong rationale for combining RFA and the PD-L1/PD-1 blockade in the clinical setting.

Keywords: Radiofrequency ablation, Programmed death-1, Programmed death ligand-1, Anti tumor immunity, Colorectal cancer liver metastases

Abstract
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought. In many cases, the effectiveness of classic therapies is heavily influenced by the status of the underlying antitumor-immunity. On the other hand, immunotherapies have shown better outcome when combined with tumor reductive therapies, not only due to the combined effects of tumor killing by each therapy but also because of a synergy between the two. Many clinical observations can be explained once we start to look at these classic therapies from an immunity standpoint. We have seen their direct effect on tumor antigen in vivo that they impact antitumor immunity more than we have realized. In turn, antitumor immunity contributes to tumor control and destruction as well. This review will take the immunological view of the classic therapies and summarize historical as well as recent findings in animal and clinical studies to make the argument that most of the cancer treatments exert their ultimate efficacy through antitumor immunity.

Keywords: cancer reductive therapy, cancer immunotherapy, targeted therapy, tumor antigen, immune checkpoint therapy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589695/

INTRODUCTION
The evolution of cancer therapy is diverse, and continues to be expanded. Tumor reductive therapies include classic therapies (e.g. surgery, chemotherapy, and radiation therapy), modern local and systemic treatment modalities, (e.g. radiation frequency ablation (RFA), local transarterial chemoembolization (TACE), high intensity focused ultrasound (HIFU)), and drugs that target specific molecules in the cancer cells). All cancer reductive therapies have only one objective: to reduce tumor burden through direct killing of tumor cells. A new category of cancer treatment, immunotherapy, emerged in the last few years and they are categorized separately from cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies, such as lymphokine-activated killer (LAK) and chimeric antigen receptor T cells CAR-T) and immune checkpoint inhibitors, such as anti-program cell death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA-4). Other modes of tumor destruction have come into clinical use with time. Examples range from older modalities such as radiation frequency ablation (RFA) to novel techniques such as irreversible electroporation (i.e. NanoKnife). With each new piece of oncology knowledge gained, a multitude of questions follow.