There has been lots of talk of PD1 check point meds being combined with ablation techniques and in therory the ablation aiding the Med to focus on the ablated tumor and or adding systemic boosting metabolic wise , along with and in addition to the Pd1 med(s) to metastic out lying distant tumors.
In looking at our microwave ablated liver tumor, and our LITT treated brain tumor,our reduction to those 2 tumors has been minimal compared to the untreated tumors while taking Opdivo ,
However ,stable to slight decrease is still awesome news ,
And we will be forever thankful for that !
This is my effort to begin to understand the process of immune response with ablations .
Any corrections encouraged
Abstract
Percutaneous image-guided ablation is an increasingly common treatment for a multitude of solid organ malignancies. While historically these techniques have been restricted to the management of small, unresectable tumors, there is an expanding appreciation for the systemic effects these locoregional interventions can cause. In this review, we summarize the mechanisms of action for the most common thermal ablation modalities and highlight the key advances in knowledge regarding the interactions between thermal ablation and the immune system.
So a patient has had RFA, microwave and or cryoblation of a tumor and or tumors
After the precieved success ,
2. Mechanisms of Action for Clinical Ablative Therapies
Then begins --
"3. Requirements for Acquired Immune System Activation
When cell death occurs, the “first responders” are typically representatives of the innate immune system, including neutrophils, macrophages, and natural killer (NK) cells. This is followed by the more robust and sustained acquired immune response. However, there are four requirements for activating the acquired immune system: antigen presentation, antigen recognition by T-cells, interaction of costimulatory molecules, and the presence of danger signals [24]. Cell necrosis results in the spillage of intracellular antigens that were previously invisible from the immune system. These antigens are acquired by antigen presenting cells, of which dendritic cells (DCs) are the most important. Dendritic cells then localize to regional lymph nodes, where they present antigens to T-cells through major histocompatibility complex (MHC) molecules. Recognition of the antigen by the T-cell is necessary but not sufficient for T-cell proliferation and survival. Without concomitant costimulation, T-cells may undergo anergy and cell death. Costimulation refers to interactions between non-antigen-specific markers on the DC and T-cell, specifically CD28 on T-cells and the B7 molecules (also known as CD80 and CD86) on DCs. Alternatively, binding of the inhibitory signaling molecule CTLA-4 on the T-cell’s surface with CD80 and CD86 functions as an “off” switch, inactivating the T-cell [25]. Finally, for DCs to activate T-cells, they themselves must become activated. Based on the “danger theory,” this occurs following the exposure of DCs to damage-associated molecular patterns, of which many have been proposed, including uric acid, heat-shock proteins (HSPs), and various cytokines [26]."
"It is important to note that antigen presentation may not occur after apoptotic damage because phagocytosis shields intracellular contents; moreover, if antigen presentation does occur, the lack of associated “danger” signals with apoptosis can lead to immune tolerance [27]. As such, the ratio of apoptosis to necrosis following thermal ablation is critical for subsequent acquired immune system activation
27.T. A. Ferguson, J. Choi, and D. R. Green, “Armed response: how dying cells influence T-cell functions,” Immunological Reviews, vol. 241, no. 1, pp. 77–88, 2011. View at Publisher · View at Google Scholar · View at Scopus
4. Interactions between Thermal Ablation and the Immune System
A relationship between thermal therapies and the immune system has been recognized since the 1960s, when an antibody response was seen following cryotherapy in a rabbit model [28]. Of the existing thermal ablation techniques, the two modalities with the most well established immune interactions are RFA and cryoablation (Table 1). While HIFU [29, 30] and MWA have been shown to elicit an immune response, the magnitude of the response appears to be far greater with RFA and cryoablation [2].
Following heat-based ablation, numerous intracellular components that stimulate the innate immune system and can activate the acquired immune system are released (Figure 1). These include RNA, DNA, HSPs, and uric acid, as well as inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) [31–34]. HSPs are common within tumor cells and are released during necrosis [35] as well as hyperthermia at 60°C [36]. Intracellularly, HSPs serve to prevent cell death by inhibiting apoptosis [36]. Once in the extracellular space, however, they drive the acquired immune response via several mechanisms, HSPs chaperone antigens to DCs for presentation, and they also function as danger signals to facilitate DC activation [35, 37–40]. HSP70 in particular has been implicated in the immune response to ablation therapy, and HSP70 levels are elevated in the serum of patients following RFA [41, 42].
Figure 1: Thermal ablation and the proposed mechanisms for immunostimulation and oncogenesis in the liver. In the central heating zone, temperatures > 50°C cause coagulation necrosis. In the adjacent peripheral heating zone, lethal hyperthermia temperatures may not be achieved, leading to either necrosis, apoptosis, or recovery. In this zone, hyperemia results in increased oxygen delivery, and cell death results in the release of cytokines and other immune stimulatory factors such as heat-shock protein 70 (HSP70). As a result, either immunostimulation due to T-cell activation or immunosuppression due to T-cell anergy in the setting of apoptosis may occur. Sublethal thermal injury to the adjacent hepatocytes causes the release of additional growth factors such as c-Met that can cause systemic tumor growth stimulation.
RFA also reduces levels of regulatory T-cells () [32]. By suppressing these immunosuppressive cells, RFA may diminish immune tolerance to tumor cells, resulting in a more tumoricidal immune response. Indeed, levels of tumor-specific T-cells have been seen after RFA, and there is a survival benefit associated with higher levels of these cells [43, 44]. For example, intratumoral accumulation of CD8+ T-cells is associated with improved survival in patients with hepatocellular carcinoma who undergo resection surgery [45]. RFA has been shown to also result in an increase in tumor-specific antibodies, CD4+ cells, and CD8+ cells weeks to months after the ablation procedure [46]. On the other hand, since the early days of RFA, anecdotal reports of patients rapidly developing metastases following an ablation procedure have been described, and recently, an immunologic mechanism for these observations has begun to be elucidated. Indeed, RFA has been shown to cause distant tumor growth following hepatic ablation procedures in preclinical primary and metastatic liver cancer models [3, 47–50]. A key factor for these deleterious effects appears to be the response of the liver parenchyma that is included in the ablation zone. In those areas, elevated levels of HSPs, hypoxia induced factor-1α (HIF-1α), and other cytokines have been identified [34, 49, 51–53]. In an intriguing experiment, Ahmed et al. [47] performed RFA on a small portion of normal liver in a rat model and demonstrated accelerated growth in distant breast cancer xenografts compared to partial hepatectomy or sham surgery controls. This oncogenic response to RFA may be mediated by activation of hepatocyte regeneration signaling pathways by the heat-injured liver parenchyma, as inhibition of the hepatocyte growth factor/c-Met axis abrogates the accelerated tumor growth. Furthermore, IL-6 is an important driver of perilesional infiltration of immune cells: IL-6 knockout mice do not experience this infiltrative effect after ablation [3, 54]. Anti-IL-6 siRNA has been shown to suppress RFA-induced IL-6 production and its downstream oncogenic effects [54]. It is important to note, however, that while there is a growing body of preclinical data regarding the oncogenic impact of RFA, from a clinical standpoint, RFA has not been shown to worsen survival compared to untreated patients [48].
4.2. Cryoablation
The abscopal effect of cryotherapy has been reported as early as the 1970s [55, 56]. The concept of “cryoimmunology” originated in the 1960s when it was observed that serum anti-tumor antibodies develop after cryoablation [24, 57]. Anecdotal reports of the abscopal effect of cryotherapy in humans followed shortly thereafter in the 1970s [58]. Around the 1970s, it was also observed that cryotherapy can cause immunosuppression in rats. Leaving the bulk of the tumor in the animal was seen to result in slower tumor regression compared to regression after only a small amount of tissue remained [57]. Early studies also showed that cytotoxicity after cryoablation was tumor specific; that is, the lymphocytes harvested after cryoablation did not attack other tumor types. For example, cryoablation has been shown to confer resistance to rechallenge: in xenograft models, repeat delivery of tumor cells was less effective following cryoablation versus surgery performed on the initial tumor [57, 59–61]; this protection is tumor specific, as there was no prevention of tumor growth following challenge with another tumor cell line. Cryoablation induces a much greater postablative immune response relative to RFA or MWA. This can be seen in greatly elevated levels of IL-1, IL-6, NFκB, and TNF-α after cryoablation compared to the case after RF and MW [33, 34, 62, 63]. In comparative animal studies, the degree of DC antigen loading is greater with cryoablation versus RFA [9]. The proposed reason for this variation in immune activation is that hyperthermia based methods cause protein denaturation, reducing the number of intact antigens. Also, heat causes tissue coagulation and by doing so reduces the amount of intracellular contents that spill into circulation. Freezing, on the other hand, maintains cellular ultrastructure while increasing the permeability of plasma membranes. Also, it is for these reasons that we observe the phenomenon of cryoshock. Cryoablation causes the release of inflammatory intracellular debris, causing release of cytokines that can result in systemic inflammatory response syndrome (SIRS) [63]. A similar phenomenon is not observed in hyperthermia based modalities
Abscopal effect
From Wikipedia, the free encyclopedia
Proposed mechanism of the abscopal effect, mediated by the immune system. Here, local radiation causes tumor cell death, which is followed by adaptive immune system recognition, not unlike a vaccine.
The abscopal effect is a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only a shrinking of the treated tumor, but also a shrinking of tumors outside the scope of the localized treatment. R.H. Mole proposed the term “abscopal” (‘ab’ - away from, ‘scopus’ - target) in 1953 to refer to radiation’s effects “at a distance from the irradiated volume but within the same organism.”[1] Initially associated with single-tumor, localized radiation therapy, the term has also come to encompass other types of localized treatments such as electroporation and intra-tumoral injection of therapeutics. While this phenomenon is extremely rare, its effect on the cancer can be stunning, leading to the disappearance of malignant growths throughout the entire body. Such success has been described for a variety of cancers, including melanoma, cutaneous lymphomas, and kidney cancer.
Scientists are not certain how the abscopal effect works to eliminate cancer in patients. Studies in mice suggest that the effect may depend upon activation of the immune system. In a case study reported at Memorial Sloan-Kettering Cancer Center in New York City,[2] changes in a metastatic melanoma patient’s immune system were measured over the course of treatment. The team observed changes in tumor-directed antibody levels and immune cell populations that occurred at the time of the abscopal effect. These findings support the idea that a localized treatment may broadly stimulate the immune system to fight cancer. At this time, various immune system cells, including T-cells and dendritic cells, are believed to play a primary role.
Effects in tissues adjacent to the irradiated area are bystander effects and are not necessarily mediated by the same mechanisms as abscopal effects.
