Metastatic disease is the leading cause of death in cancer patients. Metastasis formation involves a cascade of events for which the underlying mechanisms are still poorly understood. During the metastatic cascade, cancer cells tightly interact with the immune system and they influence each other, both in the tumor microenvironment and systemically. The crosstalk between cancer and immune cells adds another layer of complexity to our understanding of metastasis formation, but at the same time opens new therapeutic opportunities for cancer patients. The intensifying development of immunotherapeutic strategies calls for a better understanding of immune regulation of metastasis in order to maximize the therapeutic benefit for patients with metastatic disease. In this Review and accompanying poster, we describe the main mechanisms of immune regulation of metastasis that have been reported to date, and present promising immunotherapeutic options that are currently available, or may become so in the near future, to tackle metastasis.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC. The subpopulation of monocytic MDSC (m-MDSC) was the most affected by R848 treatment with an up to 5-fold decrease in the tumor. We found that TLR7 stimulation in tumor-bearing mice led to a maturation and differentiation of MDSC with upregulation of the surface molecules CD11c, F4/80, MHC-I, and MHC-II. MDSC treated with R848 lost their immunosuppressive function and acquired instead an antigen-presenting phenotype with the capability to induce specific Tcell proliferation. Importantly, we found that MDSC co-injected s.c. with CT26 tumor cells lost their ability to support tumor growth after pretreatment with R848. Our results demonstrate that treatment of tumorbearing mice with a TLR7/8 agonist acts directly on MDSC to induce their maturation and leads them to acquire a non-suppressive status. Considering the obstacles posed by MDSC for cancer immunotherapy, targeting these cells by a TLR7/8 agonist may improve immune responses against cancer.

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Lymphoma is the most common malignancy arising in the ocular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles. Ocular adnexal lymphoma (OAL) accounts for 1%-2% of non-Hodgkin lymphoma and 5%-15% of extranodal lymphoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the various lymphoma variants that could arise in the ocular adnexa, marginal zone B-cell lymphoma (OA-MZL) is the most common one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B-cell lymphoma and mantle cell lymphoma. Additional lymphoma entities, like T-cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Because they are so rare, related literature mostly consists of anecdotal cases included within series focused on OA-MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, behavior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommendations for therapeutic management. The Oncologist 2013;18: 876 -884 Implications for Practice: The vast majority of literature's data on ocular adnexa lymphomas focus on the most frequent herein encountered histotype, i.e., marginal zone B-cell lymphoma. However, when a physician encounters less common histologies in this anatomical site, difficulties in their recognition and management may arise, because these tumors are usually reported as minor groups within large series describing marginal zone B-cell lymphomas or under case report format. The present review aims to offer a comprehensive, easily accessible review on these uncommon histologies in order to collect and present available pathologic, clinical, and therapeutic data other than providing own authors' experience in individual considered entities.