Introduction to thermal therapy and immunotherapy: at the crossroads of new discovery

We are very pleased to publish a significant and diverse collection of primary studies and reviews in this special issue entitled Thermal Therapy and Immunotherapy: at the Crossroads of New Discovery. We thank Boston Scientific Corporation for financially supporting this issue and all authors for their contributions.

There is a long history of thermal therapy research and clinical application using both heat and cold but impacts on the immune system have generally not been the focus of this research. For most of the twentieth century the immune system was understood to be important for protecting us from infectious disease and, when appropriate control fails, causing autoimmune disease. As the tools of molecular and cellular biology were applied to the immune system it has become clear that the immune system is important not just in infectious disease and autoimmunity, but in almost every pathology.

Over 120 years ago, studies in patients with cancer done by William Coley showed that immune stimulation by bacteria could generate remission in a small but significant fraction of unresectable metastatic cancers. Coley utilized one of the few systemic immune readouts available at the time, fever, as a biomarker of whether the treatment was likely sufficient. After a century of discussion on what if any role the immune system plays in cancer, it is now clear not only that the immune system is an integral aspect of cancer biology, but that cancer is in part a failure of the immune response, and most importantly, it is now established that the immune system can be manipulated to treat cancer. This is highlighted by the expanding revolution in clinical cancer immunotherapy with the first wave being antibodies that block immune checkpoints PD-1 and CTLA4 on T cells.

Within the thermal therapy research community there has been a distinct change of focus over recent years. With some notable exceptions, most previous interest was in eliminating treated tumors with ablative hyperthermia or cryotherapy with minimal interest in how that local ablation impacts the systemic antitumor immune response. There are multiple clinically validated thermal and cryotherapy approaches to rapidly eliminate treated tumors and they are used daily for cancer treatment. However, the unmet clinical challenge of most solid cancers is not individual tumor elimination, it is systemic treatment to block progression of metastatic disease. The intersection of physical tumor treatments such as hyperthermia, cryotherapy and radiation with immunotherapy is now of considerable interest. This special issue is one sign of the growing interest in how thermal therapies impact the immune system and most of the papers are focused on using thermal therapy as one aspect of systemic immunotherapy to treat metastatic disease.

There is considerable data that all thermal treatment modalities of tumors can have a stimulatory effect on the antitumor immune response by a variety of mechanisms, including simply releasing tumor antigens from dying tumor cells. However, on their own, the immune stimulation of thermal therapies is generally not curative for untreated tumors, and combination with other immunotherapies is how thermal therapies are expected to contribute to tumor immunotherapy. With this perspective comes many questions that need to be addressed to rationally design such combinations. Among important questions: what are the optimal thermal dose parameters and delivery methods; what are the mechanisms that impact the immune system; and how best to sequence thermal therapy with other treatments to generate optimal immunotherapy for cancer.

The issue opens with a review of “Hyperthermia and immunotherapy: clinical opportunities” by Hurwitz. This paper gives a broad view of the current state of clinical hyperthermia for cancer treatment and notes the lack of specific clinical trials utilizing combination of hyperthermia and immunotherapy and the importance of initiating such studies.

It is clear that cryotherapy for cancer, a clinically available option, is able to support antitumor immune responses. Baust et al. review the physical and biological parameters of cryotherapy and how it can generate an “abscopal effect” in which untreated tumors are reported to shrink through immune influence. The review explores concepts of how to optimize that antitumor immune response.

Lin et al. review and explore the important “fever” range hyperthermia of 39–41°C and how that affects the immune system, particularly in regard to the key step of trafficking of immune cells into sites of inflammation. One less obvious but important aspect discussed is that systemic fever range temperatures can be generated by actual fever or by whole body hyperthermia, but they have some very fundamental physiological differences. With fever, the body temperature set point has been changed to conserve heat and raise body temperature, the body physiology shifts to cause the warming. With hyperthermia, the physiological set point is still at 37^° C and the body attempts to adjust and resist the externally generated increase in temperature.

This conceptual review that touches on leukocyte trafficking is followed by a related animal model experimental study by Ito et al. investigating how local radio-frequency hyperthermia treatment of tumors influences trafficking of adoptively transferred T cells into tumors. There is considerable current research focus on adoptive T cell therapy to treat cancer, however in general, results in solid tumors have been inconsistent, at least in part because the T cells do not get into the tumors. The study depends on exceptional skill with intravital microscopy and includes a clear demonstration that the addition of hyperthermia changes ineffective adoptive T-cell therapy into highly a highly effective combinatorial immune-based therapy.

Combinatorial strategies are the basis of most cancer therapies and are rapidly expanding within cancer immunotherapy. Duval et al. explore the immunogenic effects of combining low doses of both hyperthermia and radiation and show specific relevant changes of tumor cell gene expression when both physical modalities are employed as compared to a single modality. Oei et al. contribute an interesting in vivo mouse study using a spontaneous metastatic orthotopic breast cancer model. Treatments were various combinations of iron-oxide nanoparticle mediated hyperthermia, radiation, and immune checkpoint inhibiting antibodies. The results and conclusions are extensive and complex with some simple takeaways being that heat plus radiation had very strong local effects and adding immune checkpoint therapy clearly had the strongest effect on the primary tumor. However, the impact on spontaneous metastasis, which was compared to surgery, was more complex and points the way toward further needed studies.

Singh et al. contribute a study combining focused ultrasound mediated hyperthermia with CD40 agonist antibody in a mouse cancer model. The study shows that this combination improves treatment efficacy through immune mechanisms and documents a variety of responsive immune parameters that are mechanistically implicated in that improved efficacy.

Qiao et al. report on results of a phase I clinical trial in previously treated patients with a variety of solid tumors. The study combined moderate temperature hyperthermia with autologous adoptive T cell therapy and either salvage chemotherapy or anti-PD-1 antibody therapy. The results include changes to a variety of immune biomarkers and show that the combination was safe and generated clinical responses in some of the patients.

There is more to thermal influences on the immune system than cancer involvement and Hylander and Repasky have contributed a forward-thinking review on how temperature can influence the gut microbiome. There is a rapidly developing understanding that the huge numbers of microorganisms we carry have profound influences on our physiology and pathology, including particularly strong influences on the immune system. These immune influences are perhaps best illustrated by the strong associations being reported on the impact of gut microbiome on development of autoimmune disease. There are also strong associations between gut microbiome characteristics and response to cancer immunotherapy. As outlined in this review, the impact of temperature on the gut microbiome now has clear relevance for a number of important topics in biomedical research and clinical care.