Harnessing cancer immunotherapy during the unexploited immediate perioperative period

Matzner, Pini; Sandbank, Elad; Neeman, Elad; Zmora, Oded; Gottumukkala, Vijaya; Ben‐Eliyahu, Shamgar

doi:10.1038/s41571-019-0319-9

Cited by 77 publications

(69 citation statements)

References 232 publications

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“…However, it is clear that factors related to wound healing after surgery, particularly as they utilise similar pathways of angiogenesis and control of infection, may provide evidence of the role of postoperative inflammation in the natural history of cancer [9]. More recently, there has been a call for more research looking at the immediate postoperative period as a highly influential period in determining prognosis, out of proportion to its relative length compared to the pre-operative and longer term medical period for cancer patients [45]. Understanding how postoperative complications, and by extension, the immune landscape of cancer in the perioperative period affect clinical outcomes may reveal immunotherapeutic options for cancer patients [45].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, there has been a call for more research looking at the immediate postoperative period as a highly influential period in determining prognosis, out of proportion to its relative length compared to the pre-operative and longer term medical period for cancer patients [45]. Understanding how postoperative complications, and by extension, the immune landscape of cancer in the perioperative period affect clinical outcomes may reveal immunotherapeutic options for cancer patients [45].…”

Section: Discussionmentioning

confidence: 99%

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The effect of postoperative complications on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis

Savioli

Edwards

McMillan

et al. 2020

Critical Reviews in Oncology/Hematology

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Background: This systematic review investigated the impact of complications on long term outcomes for patients with primary invasive operable breast cancer.Methods: A systematic review was performed using appropriate keywords, and meta-analysis using a random effects model completed.Results: Ten retrospective cohort studies, including 37657 patients were included. Five studies identified a relationship between wound complications, infection and pyrexia and recurrence or recurrence-free survival. Risk of recurrence, 1-year and 5-year recurrence-free survival and overall survival were related to complications, particularly for patients with poor Nottingham Prognostic Index. Five studies failed to demonstrate a relationship between complications and prognosis. Complication was found to significantly affect 5-year recurrence-free survival (HR 1.48 95% CI 1.02-2.14, p=0.04) but not recurrence (HR 2.39, 95%CI 0.94-6.07, p=0.07), with a high degree of heterogeneity among analysed studies (I2=95%).Discussion: Further research is needed to quantify the effects of postoperative complication on prognosis following surgery for breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The effect of postoperative complications on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis

Savioli

Edwards

McMillan

et al. 2020

Critical Reviews in Oncology/Hematology

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“…This may tilt the balance toward the eradication of metastases or arrest of their growth. The perioperative period harbors numerous risk factors for metastatic progression and was thus suggested to present a window of opportunity to exert a high impact on long-term cancer outcomes through various interventions [1,31,52].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

et al. 2020

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Background Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms. Results Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival. Conclusions These results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.

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“…Such a treatment can also counteract the 20 metastasis-promoting effects of surgery [52,1] and tilt the balance toward eradication of metastases or arrest of their growth. The perioperative period harbor numerous risk factors for metastatic progression, and was thus suggested to present a window of opportunity to exert high impact on long-term cancer outcomes through various interventions [1,53]. The herein findings may explain the rare but validated clinical phenomenon of spontaneous regression of metastases following PT excision.…”

Section: Discussionmentioning

confidence: 66%

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

Shaashua

Eckerling

Israeli

et al. 2020

Preprint

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Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor (PT) excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency following PT excision, and identify potential underlying mechanisms. Using MDA-MB-231 HM human breast cancer cells that 5 express highly sensitive luciferase, we were able to monitor early stages of spontaneous metastases development in BALB/c nu/nu mice. Removal of the PT caused marked regression of the smallest micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that PTsecreted factors promote early metastatic growth. Correspondingly, cancer cell conditioned 10 medium reduced apoptosis and enhanced MDA-MB-231 HM adhesion in vitro. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231 HM secretome were conducted. Results identified significant enrichment of angiogenesis, growth factors binding and activity, focal adhesion, metalloprotease regulation, and apoptosis regulation processes. Simultaneous in vivo blockade of four secreted key 15 potential mediators of these processes, IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF, arrested development of micro-metastases in the presence of the PT. Interestingly, using the public TCGA provisional dataset, high protein levels of these four factors were correlated with poor survival in a cohort of lung adenocarcinoma patients. These results demonstrate regression and latency of micro-metastases following PT excision, and a 20 crucial role for PT-secretome in promoting early metastatic stages in MDA-MB-231 HM xenografts. If generalized, such findings can suggest novel approaches to control minimal residual disease during and following PT excision.

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Harnessing cancer immunotherapy during the unexploited immediate perioperative period

Cited by 77 publications

References 232 publications

The effect of postoperative complications on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis

The effect of postoperative complications on survival and recurrence after surgery for breast cancer: A systematic review and meta-analysis

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

Spontaneous regression of micro-metastases following primary tumor excision: a critical role for primary tumor secretome

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