Tissues in Different Anatomical Sites Can Sculpt and Vary the Tumor Microenvironment to Affect Responses to Therapy

Devaud, Christel; Westwood, Jennifer A.; John, Liza B.; Flynn, Jacqueline K.; Paquet-Fifield, Sophie; Duong, Connie P.M.; Yong, Carmen S.; Pegram, Hollie J.; Stacker, Steven A.; Achen, Marc G.; Stewart, Trina J.; Snyder, Linda A.; Teng, Michele W.L.; Smyth, Mark J.; Darcy, Phillip K.; Kershaw, Michael H.

doi:10.1038/mt.2013.219

Cited by 110 publications

(136 citation statements)

References 56 publications

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“…Proof of this principle was recently provided by directly comparing the efficacy of immunotherapy on three orthotopic tumors versus their subcutaneous counterparts. This study showed that in addition to microenvironmental differences in immune cell profile and vascularity, orthotopic tumors are more immunosuppressive in nature and less sensitive to immunotherapy than subcutaneous tumors [188]. We have also learned that conventional anti-cancer therapies have both direct and indirect effects on the immune system (Figure 2).…”

Section: Discussionmentioning

confidence: 95%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Section: Discussionmentioning

confidence: 95%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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“…Only a few groups took the effort to compare the ectopic and orthotopic tumors side by side, but their groundbreaking findings did not reach the mainstream of anticancer research. For instance, it has been demonstrated that renal, colon and prostate tumors respond to immunotherapy to a much lesser extent in the orthotopic setting compared to the subcutaneous location [5]. In analogy, renal carcinoma cells were described to be more resistant to treatment with doxorubicin when inoculated into kidneys compared to subcutaneous tumors [6].…”

Section: Short Communicationmentioning

confidence: 99%

Improving Anti-cancer Immunotherapy by Simultaneous Targeting Suppressive Tumor Microenvironment

Bialkowski¹,

Thielemans²

2016

J Vaccines Vaccin

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Recent advances in immunotherapy led to a breakthrough in cancer treatment, changing the algorithms of clinical cancer management. Notwithstanding this success, numerous immune escape mechanisms significantly hamper the long-term efficacy of immunotherapy. A growing body of evidence recognizes immunosuppressive tumor microenvironment (TME) as a major obstacle for effective anti-cancer immunotherapy. It is therefore postulated that multiple pathways in TME need to be targeted in support to the induction of tumor-specific effector immune cells. Our lab has developed a novel mRNA vaccination platform allowing for induction of strong anti-tumor immune responses in the context of cervical cancer. In our recent study, using a variety of in vivo and ex vivo techniques, we observed the existence of organ-specific microenvironments that differed in their immunosuppressive capacity. We demonstrated that the particularly hostile nature of genital tract TME could be alleviated using cisplatin. This data indicated that the induction of tumor-specific T cells accompanied by a simultaneous targeting of TME is a prerequisite for the improvement of adaptive anti-cancer immunotherapies, thereby emphasizing the need for a TME-tailored immunotherapy.Keywords: Tumor microenvironment; Personalized immunotherapy; mRNA vaccine; Cisplatin Short CommunicationThe latest analyses of clinical success rates for drug development indicate a significant divergence between R&D expenses and new drug approvals. While anti-cancer drugs constitute a large majority of drug development paths, the 'Likelihood of Approval' rate for oncology (6.7%) is the lowest amongst all tested conditions [1]. One of the reasons for this status quo can be a limited predictive value of currently used animal models, particularly in the context of interactions between the host immune system and cancer cells. This can partly be due to the fact that traditionally the role of the host immune system was deemphasized giving the priority to the tumor cells [2]. As a consequence, for years the accurate recapitulation of the tumor microenvironment (TME) was underappreciated, disregarding the immune contexture as a powerful contributor to tumorigenesis [3]. Over decades, ectopically implanted tumor cell lines in syngeneic mice served as an universal model for anti-cancer drug evaluation [4]. Although such approach offered a unique possibility of in vivo therapy in the context of a fully functional immune system, the impact of the primary, orthotopic tumor location, and thus relevant microenvironment, was largely neglected. Only a few groups took the effort to compare the ectopic and orthotopic tumors side by side, but their groundbreaking findings did not reach the mainstream of anticancer research. For instance, it has been demonstrated that renal, colon and prostate tumors respond to immunotherapy to a much lesser extent in the orthotopic setting compared to the subcutaneous location [5]. In analogy, renal carcinoma cells were described to be more resistant to treatment...

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“…Following intrarenal inoculation of Renca, a primary tumor forms in the kidney at the site of inoculation, resulting in the development of spontaneous lung metastases. 20 Since we had previously found that the use of anti-CD4 mAb was more effective than anti-CD25 or anti-FR4 at depleting Treg in BALB/c mice, 14 we treated mice bearing established SC or kidney Renca tumors (11 d) by intraperitoneal injection of anti-CD4 or control antibody on days 11, 12 and 13. All control-treated tumors grew progressively, but despite initial progression of tumors, the majority of SC tumors fully regressed following Treg depletion (Fig.…”

Section: Treg Depletion Using Anti-cd4 Eradicates Established Subcutamentioning

confidence: 99%

“…20 However, we did not assess in that study whether Treg could play a role in the immunosuppressive response occurring in IK Renca tumors.…”

Section: Introductionmentioning

confidence: 95%

Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

et al. 2014

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In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3 DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8 C effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4 C T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.

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Tissues in Different Anatomical Sites Can Sculpt and Vary the Tumor Microenvironment to Affect Responses to Therapy

Cited by 110 publications

References 56 publications

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Improving Anti-cancer Immunotherapy by Simultaneous Targeting Suppressive Tumor Microenvironment

Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

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