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Combining Surgery and Immunotherapy: Turning an Immunosuppressive Effect Into a Therapeutic Opportunity

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Combining Surgery and Immunotherapy: Turning an Immunosuppressive Effect Into a Therapeutic Opportunity J Immunother Cancer: first published as 10.1186/s40425-018-0398-7 on 3 September 2018. Downloaded from Bakos et al. Journal for ImmunoTherapy of Cancer (2018) 6:86 https://doi.org/10.1186/s40425-018-0398-7 REVIEW Open Access Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity Orneala Bakos1, Christine Lawson1, Samuel Rouleau1 and Lee-Hwa Tai1,2* Abstract Background: Cancer surgery is necessary and life-saving. However, the majority of patients develop postoperative recurrence and metastasis, which are the main causes of cancer-related deaths. The postoperative stress response encompasses a broad set of physiological changes that have evolved to safeguard the host following major tissue trauma. These stress responses, however, intersect with cellular mediators and signaling pathways that contribute to cancer proliferation. Main: Previous descriptive and emerging mechanistic studies suggest that the surgery-induced prometastatic effect is linked to impairment of both innate and adaptive immunity. Existing studies that combine surgery and immunotherapies have revealed that this combination strategy is not straightforward and patients have experienced both therapeutic benefit and drawbacks. This review will specifically assess the immunological pathways that are disrupted by oncologic surgical stress and provide suggestions for rationally combining cancer surgery with immunotherapies to improve immune and treatment outcomes. Short conclusion: Given the prevalence of surgery as frontline therapy for solid cancers, the emerging data on postoperative immunosuppression and the rapid development of immunotherapy for oncologic treatment, we believe that future targeted studies of perioperative immunotherapy are warranted. Keywords: Perioperative period, Postoperative immunosuppression, Perioperative immunotherapy http://jitc.bmj.com/ Background Since the initial observation of the prometastatic ef- Solid cancers are the second leading cause of death world- fects of surgery by surgeons in 1913 [2], numerous pre- wide, accounting for 8.8 million deaths in 2016. The most clinical tumor models have demonstrated that surgical common causes of solid cancer death are cancers of lung resection contributes to the development of metastatic (1.69 million deaths), liver (788,000 deaths), colorectal disease [3, 4] with the frequency of metastatic deposits (774,000 deaths), stomach (754,000 deaths) and breast correlating with the degree of surgical trauma [3]. Des- on September 24, 2021 by guest. Protected copyright. (571,000 deaths) (WHO statistics). Major thoracic or ab- pite these early promising findings, limited mechanistic dominal surgery is the mainstay of treatment for these top advances have been made. In clinical studies, complica- 5 solid cancers to extend the patient’s life. Unfortunately, tions in the postoperative period have been shown to as- disease recurs within 5 years in the majority of these pa- sociate with increased development of metastatic disease tients and they tend to not respond to frontline therapies and poor cancer survival [5, 6]. Various perioperative [1]. Minimal residual disease are occult tumors that persist changes have been proposed to describe the promotion in the patient following curative surgery. of metastases following surgery, including tumor cell dissemination into nearby blood vessels and lymphatics * Correspondence: [email protected] [7, 8], local and systematic release of growth factors [9, 1Department of Anatomy and Cell Biology, Faculty of Medicine and Health 10], and cellular immune suppression [11–15]. Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada There is increasing mechanistic evidence to suggest pri- 2Centre de Recherche Clinique de Centre Hospitalier de l’Université de Sherbrooke (CHUS), Room 4853, 3001, 12e Avenue Nord, Sherbrooke, mary tumor surgical resection disrupts the host immune Québec J1H 5N4, Canada system. These effects lie within the “postoperative period”, © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. J Immunother Cancer: first published as 10.1186/s40425-018-0398-7 on 3 September 2018. Downloaded from Bakos et al. Journal for ImmunoTherapy of Cancer (2018) 6:86 Page 2 of 11 which lasts days [16] to weeks [16, 17] following tumor sur- the natural composition of cells in vivo, while in vitro- gical resection and has been suggested to create an im- induced cytokine readings are measured from isolated munosuppressive window for the expansion and escape of cell populations following non-physiological levels of occult tumors [11]. The postoperative period is a relatively LPS/PHA stimulation [15]. The overall effect of these short timeframe compared to the much longer duration of secreted factors is the rapid expansion of regulatory primary tumor development and progression. However, re- myeloid (myeloid derived suppressor cells - MDSC, M2 cent mechanistic studies demonstrate that this short period macrophages) and T regulatory cells (Treg) (Fig. 1). Tis- of surgery-induced immunosuppression is critically import- sue trauma, in general, triggers a number of changes in ant in shaping the probability of postoperative metastatic phenotype and function, including enhanced activation disease [11, 14, 18]. This review will focus on the innate of Tregs and expansion of MDSC. Following cancer sur- and adaptive immunological pathways that are disrupted by gery specifically, Zhou et al. detected elevated peripheral oncologic surgical stress and provide suggestions for ration- Treg levels on postoperative day 7 in breast cancer pa- ally combining cancer surgery with immunotherapies to tients undergoing radical mastectomy [22]. In cervical improve immune and treatment outcomes. cancer patients undergoing laparoscopy, elevated levels of both MDSC and Tregs lead to a Th1, Th2, Th17 and Treg Main cytokine imbalance. In these patients, perioperative Molecular and cellular mediators of postoperative multi-dose treatment with the COX-2 inhibitor Parecoxib immune suppression was found to reduce postoperative immunosuppression While surgical resection provides effective debulking through restoration of cytokine levels [23]. In contrast to treatment for solid tumors, the end-result is substantial the above studies describing expansion of Tregs, periph- tissue and vasculature trauma. This is due to unavoid- eral Treg populations obtained from ovarian cancer pa- able tumor and normal tissue dissection and the poten- tients were observed to diminish significantly at tial removal of organs during major tumor resection postoperative day 3, followed by an augmentation at day [19]. At the cellular level, surgery-induced necrotic cell 7. Furthermore, accumulation of Treg populations postop- death leads to the release of sequestered cellular factors. eratively was found to be tumor stage dependent, as pa- These factors make up the “alarmins” that alert the im- tients with early stage I/II tumors showed decrease Treg mune system to the presence of tissue damage. Follow- population, while those with late stage III/IV tumors ex- ing the detection of alarmins by pathogen recognition hibited greater amounts by comparison [24]. receptors, innate immune cells initiate inflammatory As integral members of the innate immune system, pathways, chemotaxis, antimicrobial defenses, and adap- Natural Killer (NK)-cells are involved in the direct kill- tive immune cell responses [19]. After the early trauma ing of cells displaying abnormalities linked to infection, response to tissue injury, pro- and anti-inflammatory re- malignancy or transplantation [25, 26]. Immunosurveil- http://jitc.bmj.com/ sponses are temporally regulated by soluble mediators lance of the host by NK-cells for malignant cells results and innate and adaptive immune cells. Cellular immune in direct cytotoxicity and the production of cytokines to suppression following cancer surgery has been shown to enhance the immune response [26]. Postoperative peak at 3 days and occasionally lasting several weeks NK-cell cytotoxic dysfunction has been demonstrated in [11, 16, 17]. This suppression is multi-factorial, and is preclinical [11, 27–30] and clinical studies [11, 17, 29]. characterized by the release of growth factors (VEGF, NK-cell functional impairment is associated with progres- on September 24, 2021 by guest. Protected copyright. PDGF, TGF-β), clotting factors, stress hormones (gluco- sive metastatic disease in animal experimental models corticoids, catecholamines [20], prostaglandins [21]) and [4, 11, 31, 32]. In human patients with solid malignan- cytokines into the extracellular compartments. Com- cies, inferior NK-cell function following surgery correlates monly, Th1 cytokines are suppressed following surgery with poor prognosis [33–35]. Even with the numerous re- (decrease in IL-2, IL-12 and IFN-γ)[21], leading to a ports documenting postoperative NK-cell suppression, very shift towards Th2 immunity (increase in IL-6/8 [20, 21],
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