Improving cancer-specific outcomes in solid organ transplant recipients: Where to begin?

In an article published in this issue of Cancer, D’Arcy et al link the incidence of cancer among recipients of solid organ transplantation (SOT) in the Scientific Registry of Transplant Recipients with data from regional and statewide cancer registries to examine cancer-specific mortality for common malignancies in SOT recipients. This analysis helps to illuminate the role of immune surveillance across a broad range of malignancies and compares the incidence of cancers due to virally mediated oncogenesis (lymphoma, squamous cell carcinoma of the aerodigestive epithelium, and hepatitis-induced liver cancer) with the incidence of other malignancies. The authors’ central finding is that cancer-specific mortality is significantly increased in SOT recipients in comparison with nontransplant recipients for multiple cancers, and the increased cancer incidence is not limited to the effects of viral oncogenesis. The authors document a significant increase in common epithelial malignancies that are currently treated with immune checkpoint antibodies, including melanoma, bladder cancer, colorectal cancer, cancers of the oral cavity/pharynx, kidney cancer, and lung cancer, and this supports the hypothesis that post-SOT immunosuppression affects immune surveillance in these cancers. Provocatively, the authors also document increases in the incidence and mortality of cancers not typically responsive to immune checkpoint therapies, including breast cancer and pancreatic cancer. The findings of D’Arcy et al suggest that immune surveillance controls oncogenesis and tumor progression in a broad range of malignancies and that breast cancer and pancreatic cancer could be sensitive to drugs targeting immune surveillance pathways other than those treated with currently Food and Drug Administration–approved antibodies to CTLA4 and PD-1/PD-L1.     

Oncogenic cancer/testis antigens: prime candidates for immunotherapy

Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.     

From Immunodeficiency to Humanization: The Contribution of Mouse Models to Explore HTLV-1 Leukemogenesis

The first discovered human retrovirus, Human T-Lymphotropic Virus type 1 (HTLV-1), is responsible for an aggressive form of T cell leukemia/lymphoma. Mouse models recapitulating the leukemogenesis process have been helpful for understanding the mechanisms underlying the pathogenesis of this retroviral-induced disease. This review will focus on the recent advances in the generation of immunodeficient and human hemato-lymphoid system mice with a particular emphasis on the development of mouse models for HTLV-1-mediated pathogenesis, their present limitations and the challenges yet to be addressed.     

Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis

The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi’s sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.Phagocytosis and autophagy are two processes that deliver microbes and their constituent proteins to the lysosome for degradation, thereby contributing to the clearance of pathogens and to the presentation of peptide antigens to T cells (1, 2). However, it is not known whether endocytic internalization and lysosomal targeting of virus-encoded cell-surface receptors contributes to the control of viral infection and disease.Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of AIDS-related and other forms of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease (3–5). KS is a multifocal tumor characterized by proliferating spindle cells (possibly of endothelial origin), angiogenesis, vascular slits, erythrocyte extravasation, and inflammatory cells. Proinflammatory signaling by the dominant KS cell, the spindle cell, is considered the driving force in KS lesions (6). The risk of KSHV-associated malignancies increases with increased lytic viral replication (7–9), suggesting that KSHV-induced oncogenesis may be related to the levels of expression of viral oncoproteins.The oncogenic KSHV G protein-coupled receptor (vGPCR), encoded by the KSHV ORF74 lytic gene, is a constitutively active chemokine receptor expressed in patients with KSHV-associated tumors (10). At least in animal studies, there are strong data that vGPCR substantially contributes to the onset and progression of KSHV-associated neoplasia in vivo (11–19). Although only a small proportion of tumor cells express vGPCR (10), they are both sufficient and necessary for KSHV-induced sarcomagenesis. The endothelial-specific expression of vGPCR (but of neither KSHV latent genes, such as vCyclin, vFlip, and Kaposin, nor other KSHV lytic genes, such as vBcl-2 or vIRF1) or injection of murine endothelial cells stably expressing vGPCR (but not other KSHV genes, such as vCyclin, vFlip, Kaposin, LANA, vIL-6, vBcl-2, and K1) causes multifocal KS-like tumors in mice (15, 18). Furthermore, injection of a small number of endothelial cells expressing vGPCR increases the tumorigenic potential, in a paracrine fashion, of endothelial cells expressing other KSHV latent genes (vCyclin and vFlip), whereas eradication of the small number of vGPCR-expressing cells in established mix-cell tumors induces tumor regression (15, 18). Moreover, in a nude mouse model of KS driven by transfection of a KSHV bacterial artificial chromosome into bone marrow endothelial-lineage cells, siRNA interference (RNAi)-mediated suppression of vGPCR expression dramatically reduces angiogenesis and tumor formation (19). In addition, immunocompetent mice that transgenically express doxycycline (DOX)-inducible KSHV GPCR in endothelial cells (hereafter referred to as ikGPCR⁺) manifest lesions that strongly resemble human Kaposi’s sarcoma (16, 17). Importantly, the progression of lesions in ikGPCR⁺ mice is reversible because DOX withdrawal leads to significant regression of vGPCR-induced lesions (17), suggesting that vGPCR-driven oncogenesis is highly dependent on sustained vGPCR expression and signaling.Based on these previous observations in animal models regarding KSHV GPCR and oncogenesis, we developed the hypothesis that cell-intrinsic mechanisms that decrease vGPCR protein levels may function as an important host defense mechanism for controlling viral oncogenesis. Recently, we showed that the autophagy protein, Beclin 2 (but not the related autophagy protein Beclin 1) is essential for the endolysosomal degradation of certain cellular GPCRs that are regulated by GASP1 rather than by ubiquitination and the endosomal sorting complexes required for the transport pathway (20). This function of Beclin 2, but not Beclin 1, regulates mouse brain cannabinoid receptor levels and metabolism in vivo (20). Therefore, we investigated whether Beclin 2 may play a role in the endolysosomal degradation of viral GPCRs and thereby represent an important host defense mechanism against KSHV GPCR-induced oncogenic effects. Our results demonstrate a crucial role for Beclin 2 in KSHV GPCR trafficking, proinflammatory signaling, and in vivo tumorigenicity, and thus represent a previously undescribed role for endolysosomal trafficking in innate immunity and the control of viral GPCR-driven oncogenesis.     

Danish patients with untreated multiple myeloma do not harbour human herpesvirus 8

The role of human herpesvirus 8 (HHV-8) in multiple myeloma (MM) remains controversial. We examined 15 Danish MM patients before cytoreductive therapy. Mononuclear cells isolated from peripheral blood and bone marrow aspirates, as well as long-term cultured bone marrow stromal cells, were assayed for the presence of HHV-8 DNA. All material was tested by three simple unnested polymerase chain reaction (PCR) assays (amplifying regions of ORF26, ORFK1 and ORF75) and two nested PCR assays (amplifying regions of ORF26). HHV-8 was not demonstrated in any of the samples. Our findings do not suggest an association between HHV-8 and MM in the Danish population.     

Human papillomavirus (HPV) type 6 and 16 DNA sequences in bronchial squamous cell carcinomas demonstrated by in situ DNA hybridization

A series of 131 routinely processed, paraffin-embedded biopsy specimens derived from the same number of patients with a bronchial squamous cell carcinoma were analyzed using in situ DNA-hybridization technique with a probe cocktail containing³⁵S-labeled human papillomavirus (HPV) DNA of types 6, 11, 16, 18, and 30. The 12 carcinomas shown to contain HPV DNA by the probe cocktail were subjected to in situ hybridization with the specific HPV DNA probes applied separately under high stringency conditions. HPV DNA could be found in 9 of these carcinomas; 2 cases contained HPV 6 DNA and 7 hybridized with HPV 16 DNA. The role of HPV in the development of bronchial squamous cell carcinoma is discussed in the light of the previously established morphologic evidence as well as the increasing number of reports on malignant transformation of the respiratory tract HPV lesions. The present findings of HPV DNA sequences provide further support to the concept of HPV as a potential causative agent of some bronchial squamous cell carcinomas, possibly acting synergistically with chemical or physical carcinogens. As in the genital tract, it seems clear that a respiratory tract infection by “low-risk” HPV types 6 and 11 by no means excludes the possibility of malignancy, so far ascribed almost exclusively to the “high-risk” type HPV 16.