The Role of the Tumour Microenvironment in Immunotherapy

2412 S Gasser et al. Tumour microenvironment 24:12 T283–T295 Thematic Review and therapeutic implications The role of the tumour microenvironment in immunotherapy Stephan Gasser1,2, Lina H K Lim3 and Florence S G Cheung3 1Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Roche Glycart AG, Schlieren, Switzerland Correspondence 2 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, NUS Immunology should be addressed Programme, Centre for Life Sciences, National University of Singapore, Singapore to S Gasser or F S G Cheung 3 Department of Physiology, Yong Loo Lin School of Medicine, NUS Immunology Programme, Centre for Email Life Sciences, National University of Singapore, Singapore [email protected] or [email protected] Abstract Recent success in immunomodulating strategies in lung cancer and melanoma has Key Words prompted much enthusiasm in their potential to treat other advanced solid malignancies. f pancreatic cancer However, their applications have shown variable success and are even ineffective f thyroid cancer against some tumours. The efficiency of immunotherapies relies on an immunogenic f immunotherapy tumour microenvironment. The current field of cancer immunology has focused on f tumour microenvironment understanding the interaction of cancer and host immune cells to break the state of f endometrial cancer immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic Endocrine-Related Cancer Endocrine-Related outcome. We also discuss insights into recent multimodal therapeutic approaches that Endocrine-Related Cancer target tumour immune evasion and suppression to restore anti-tumour immunity. (2017) 24, T283–T295 Introduction Recent advances in immunotherapy have presented prognostic significance of immune signatures that may opportunities to eliminate cancers that were not achieved guide immunotherapies for endocrine-related cancers. with previous standard of care therapies (Delitto et al. 2016). Immune checkpoint inhibitor treatment has shown to be a tolerable therapy delivering very promising results Factors that correlate with responses to in treating many cancer types including melanomas and cancer immunotherapies lung cancer (Delitto et al. 2016, Rafei et al. 2017). However, Tumour histology recurrence of cancers and variable success among different cancers are not uncommon. Even in responsive The immune profile of a patient is influenced by cancers, the immune checkpoint inhibitor success rate intrinsic factors including genetic composition of the is often below 50% of patients (Chen & Mellman 2017). tumour and the expression of proinflammatory factors These inefficiencies and variability emphasise our lack of (Chen & Mellman 2017). In addition, extrinsic factors understanding of the immunologic events involved in such as prior or concurrent infections, age, microbiota the tumour microenvironment. In this review, we will or other environmental factors are likely important summarise our knowledge of the immune responses in determinates in the response to immunotherapies endocrine cancers, with new insights in predictive and (Chen & Mellman 2017). http://erc.endocrinology-journals.org © 2017 Society for Endocrinology This paper forms part of a special section on Immunotherapy and Cancer. DOI: 10.1530/ERC-17-0146 Published by Bioscientifica Ltd. The guest editors for this section were Joanne Y Y Ngeow and Laura S Ward. Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 06:28:41PM via free access 10.1530/ERC-17-0146 Thematic Review S Gasser et al. Tumour microenvironment 24:12 T284 and therapeutic implications Recent clinical findings using checkpoint inhibitors tumours and many immune excluded tumours recruit suggest that the degree of T cell infiltration in the tumour MDSCs and secrete TGF-β, which creates a reactive is an important predictor of response of patients to immunosuppressive stroma that lacks an inflammatory cancer immunotherapy (Teng et al. 2015). Furthermore, milieu required for T cell infiltration and activation the phenotype of T cells and their localisation within (Hegde et al. 2016). In these types of cancers, checkpoint the tumour microenvironment are likely to impact the inhibitor immunotherapy responses are uncommon results (Teng et al. 2015, Chen & Mellman 2017). In an (Tothill et al. 2008, Calon et al. 2015, Ryner et al. attempt to categorise cancers according to their immune 2015). Non-inflamed tumours are also characterised by phenotype, three broad types of cancer were suggested cytokines and cell types that are associated with immune to exist: Inflamed tumours, immune excluded and suppression and tolerance, such as regulatory T cells, immunologically ignorant, also referred to as immune MDSCs and M2 macrophages (Chen & Mellman 2017). deserts (Hegde et al. 2016). Inflamed tumours with pre- M1 and M2 macrophages promote Th1 and Th2 responses, existing immunity are characterised by the presence of respectively, where M1 macrophages initially fight to tumour infiltrating lymphocytes (TILs) with high density sterilise a wound in the case of an infection followed by of functional IFN-γ-secreting CD8+ T cells and CD4+ T cells. M2 macrophages, which secrete growth factors to promote These T cells often express inhibitory receptors such as growth, proliferation, wound healing and the induction PD-1 and CTLA-4 and other markers indicative of an of anti-inflammatory regulatory T cells (Cao et al. 2010, exhausted phenotype. The inflamed phenotype correlates Mills 2012). Cancers with insignificant levels of specific in some cancers with genetic instability and occurrence antigen are analogous to sterile wounds. The presence of of tumour-specific mutations in peptides that can be M2 macrophages promotes tumour growth while tumour- recognised by T cells, so-called neoantigens (Schumacher secreted factors such as TGF-β and prostaglandins inhibit & Schreiber 2015, Hegde et al. 2016). Inflamed tumours the presence of M1 macrophages and maintain wound are also characterised by the increased expression of healing M2 macrophages at tumour sites, shielding the proinflammatory cytokines including interleukin-1β tumour from T cells (Mills 2012). Other non-inflamed (IL-1), IL-2, IL-12, IL-23 and TNF-α (Chen & Mellman tumours show minimal infiltration of immune cells or 2017). Current checkpoint inhibitor therapies act by expression of immune-related genes possibly because they reinforcement of pre-existing T cell anti-tumour responses are non-immunogenic or represent early immune escape and are therefore most effective in inflamed tumours. In mutants. Tumours with immune desert phenotype are Endocrine-Related Cancer Endocrine-Related the presence of an active T cell tumour response, IFN-γ rare responders to checkpoint inhibitor therapies. produced by T cells and other immune cells upregulate Tumours with higher mutation and neoantigen the expression of PD-L1, which counters T cell receptor burden correlate with durable clinical benefit to and CD28-mediated activation signals of T cells (Hui et al. checkpoint inhibitor therapies. In addition, neoantigen 2017, Kamphorst et al. 2017). In clinical studies of PD-1 signatures for predicting therapy responses are also or PD-L1 antagonists, high T cell density and the adaptive beginning to emerge (Snyder et al. 2014, Rizvi et al. 2015, increase of PD-L1 expression on tumour and immune Van Allen et al. 2015). In agreement with these findings, cells are often used as features of an active anti-tumour patients with DNA repair pathway deficiencies, another T cell response (Chen & Mellman 2017). Other predictive determinant of mutational burden, were also associated biomarkers that correlate with active cellular immunity with better response (Le et al. 2015, Rizvi et al. 2015). include the expression of granzymes in T cells and chemokines such as C-X-C motif ligand 9 (CXCL9) and Role of tumour mutational load in cancer immunity CXCL10 (Chen et al. 2012). Although a response to PD-L1 inhibitor therapy is most common in inflamed tumours, A number of recent publications found correlations it is not assured, suggesting that immune cell infiltration between the mutational load uniquely present in cancer is necessary but may not be sufficient for an effective cells (neoantigens) and T cell infiltration of tumours anti-cancer response (Chen & Mellman 2017). Myeloid- (Brown et al. 2015, Li et al. 2016, Senbabaoglu et al. derived suppressor cells (MDSCs) are premature myeloid 2016). High-throughput epitope screening of cancer progenitor cells produced that suppress T cell function. mutanomes revealed that only a small fraction of The expansion of MDSCs is further promoted by tumour- mutated peptides in cancer cells produced T cell reactivity derived cytokines (Delitto et al. 2016). Some inflamed (Lu et al. 2014, Yadav et al. 2014, Linnemann et al. 2015, http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0146 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 06:28:41PM via free access Thematic Review S Gasser et al. Tumour microenvironment 24:12 T285 and therapeutic implications Schumacher & Schreiber 2015). The parameters that are derived from gene products that are expendable define immunogenic peptides are not well

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