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Letter from the Editor

Dear JITC Readers,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

JITC Editor Picks

HUMAN SOFT TISSUE SARCOMAS HARBOR AN INTRATUMORAL VIRAL MICROBIOME WHICH IS LINKED WITH NATURAL KILLER CELL INFILTRATE AND PROGNOSIS

Lauren M Perry, Sylvia M Cruz, Kara T Kleber, Sean J Judge, Morgan A Darrow, Louis B Jones, Ugur N Basmaci, Nikhil Joshi, Matthew L Settles, Blythe P Durbin-Johnson, Alicia A Gingrich, Arta Monir Monjazeb, Janai Carr-Ascher, Steve W Thorpe, William J Murphy, Jonathan A Eisen, Robert J Canter

Journal for ImmunoTherapy of Cancer 2023;11:e004285 (4 January 2023)

RESEARCH

Summary:

Interactions between cancer, the immune system, and the microbiome are known to shape anti-tumor immunity, and specific tumor microbiota have been described for breast, lung, and colon cancers as well as melanoma. Whether tumors in tissues with no exposure to the outside world also harbor microbiomes is an open question. Analyzing samples from 15 patients with soft tissue sarcomas undergoing perioperative radiotherapy and surgery, Lauren M Perry and colleagues provide evidence for the presence of intratumoral bacteria and viruses and associations with the tumor immune infiltrate as well as prognosis. High alpha diversity was observed in the majority of samples taken at the time of diagnosis, with more than 20 bacterial families identified. The makeup of the intratumoral microbiome was distinct from the constitution of the fecal and skin microbiomes and did not significantly change after radiotherapy. Beta diversity of the baseline samples was related to oncologic outcomes, but not significantly associated with any known prognostic factors for soft tissue sarcomas. Intriguingly, one patient harbored a more than 90% relative abundance of human herpesvirus 6. In the broader cohort, abundance of intratumoral viruses correlated with natural killer (NK) cell infiltration. An association between NK cell density and metastasis free survival as well as overall survival was observed in the original study population as well as a second group of 29 patients with soft tissue sarcoma from the same institution. These data demonstrate that microbes colonize even tissues considered to be sterile and raise the possibility of a link between intratumoral viruses and antitumor immunity.

TACEDINALINE (CI-994), A CLASS I HDAC INHIBITOR, TARGETS INTRINSIC TUMOR GROWTH AND LEPTOMENINGEAL DISSEMINATION IN MYC-DRIVEN MEDULLOBLASTOMA WHILE MAKING THEM SUSCEPTIBLE TO ANTI-CD47-INDUCED MACROPHAGE PHAGOCYTOSIS VIA NF-KB-TGM2 DRIVEN TUMOR INFLAMMATION

Viktoria Marquardt, Johanna Theruvath, David Pauck, Daniel Picard, Nan Qin, Lena Blümel, Mara Maue, Jasmin Bartl, Ulvi Ahmadov, Maike Langini, Frauke-Dorothee Meyer, Allison Cole, Joselyn Cruz-Cruz, Claus M Graef, Matthias Wölfl, Till Milde, Olaf Witt, Anat Erdreich-Epstein, Gabriel Leprivier, Ulf Kahlert, Anja Stefanski, Kai Stühler, Stephen T Keir, Darell D Bigner, Julia Hauer, Thomas Beez, Christiane B Knobbe-Thomsen, Ute Fischer, Jörg Felsberg, Finn K Hansen, Rajeev Vibhakar, Sujatha Venkatraman, Samuel H Cheshier, Guido Reifenberger, Arndt Borkhardt, Thomas Kurz, Marc Remke, Siddhartha Mitra

Journal for ImmunoTherapy of Cancer 2023;11:e005871 (13 January 2023)

RESEARCH

Summary:

Brain tumors are characterized by low mutational loads, immune evasion, and immunosuppressive tumor microenvironments, and few treatment options are available for children with MYC-driven medulloblastoma. Viktoria Marquardt and colleagues show that epigenetic modulation impairs MYC-driven medulloblastoma tumor growth and metastasis in murine models while increasing susceptibility to innate immune elimination. A targeted screen and rescreen of 78 inhibitors of epigenetic writers, readers, erasers, and transcriptional regulators revealed the class I histone deacetylase inhibitor tacedinaline (CI-994) as a significant inducer of apoptosis in MYC-driven medulloblastoma and minimal activity in non-MYC-driven cancer cell lines or noncancerous cells. Treatment with CI-944 reduced MYC mRNA and protein levels in multiple cell lines, while enhancing expression of nuclear factor kappa B pathway-related genes as well as surface exposure of the “eat me” signal calreticulin. In two murine models or MYC-driven medulloblastoma, CI-994 treatment was associated with an increase in tumor-infiltrating M1 macrophages as well as slower tumor growth, prolonged survival, and reduced metastases. Combination treatment with CI-994 and a macrophage checkpoint inhibitor, an anti-CD47 monoclonal antibody, resulted in significantly prolonged survival compared to either monotherapy. These findings shine new light on epigenetic regulation of innate immune surveillance in MYC-driven medulloblastoma and provide rationale for investigation of future combination immunotherapy approaches in this challenging-to-treat disease. 

T LYMPHOCYTES INDUCE HUMAN CANCER CELLS DERIVED FROM SOLID MALIGNANT TUMORS TO SECRETE GALECTIN-9 WHICH FACILITATES IMMUNOSUPPRESSION IN COOPERATION WITH OTHER IMMUNE CHECKPOINT PROTEINS

Stephanie Schlichtner, Inna M Yasinska, Gurprit S Lall, Steffen M Berger, Sabrina Ruggiero, Dietmar Cholewa, Nijas Aliu, Bernhard F Gibbs, Elizaveta Fasler-Kan, Vadim V Sumbayev

Journal for ImmunoTherapy of Cancer 2023;11:e005714  (4 January 2023)

Summary:

Galectin-9 impairs T cell and natural killer cell cytotoxicity through interactions with TIM-3 and VISTA and is highly expressed in many malignancies including breast, lung and colorectal cancer. Solid tumor cells at rest, however, secrete minimal galectin-9 and the protein lacks a secretion signal. Stephanie Schlichtner et al provide the first evidence that T cells induce secretion of galectin-9 and furthermore show that the soluble form of the protein inhibits T cell cytotoxicity. In coculture experiments with lines derived from MCF-7 breast cancer cells, WT3ab Wilms tumor cells, G401 kidney rhabdoid tumor cells, and LN-18 high grade glioblastoma cells, significant amounts of galectin-9 were released into the supernatant only when T cells were present. CD4 or CD8 neutralizing antibodies had minimal effect on galectin-9 secretion. Secreted galectin-9 co-immunoprecipitated with TIM-3 or VISTA. Pharmacologic blockade of lysosomal proteases and matrix metalloproteinases revealed two independent pathways for galectin-9 secretion: PKC-dependent translocation followed by shedding and autophagy followed by lysosomal exocytosis. Neutralization of galectin-9 or VISTA impaired releases of IL-2 and granzyme-B by T cells cocultured with cancer cells, with a concomitant reduction in target cell killing. Human galectin-9 impaired cytotoxicity of murine T cells and mice subcutaneously injected with human cancer cells had high serum levels of human galectin-9. The findings add important insight into the mechanisms of immune suppression by the checkpoint ligand galectin-9, which may be leveraged for future therapeutic targeting.

INTRAVESICAL BCG IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER INDUCES TRAINED IMMUNITY AND DECREASES RESPIRATORY INFECTIONS

Jelmer H van Puffelen, Boris Novakovic, Liesbeth van Emst, Denise Kooper, Tahlita C M Zuiverloon, Ursula T H Oldenhof, J Alfred Witjes, Tessel E Galesloot, Alina Vrieling, Katja K H Aben, Lambertus A L M Kiemeney, Egbert Oosterwijk, Mihai G Netea, Joost L Boormans, Antoine G van der Heijden, Leo A B Joosten, Sita H Vermeulen

Journal for ImmunoTherapy of Cancer 2023;11:e005518 (24 January 2023)

RESEARCH

Summary:

Intravesical instillation of the Mycobacterium bovis strain Bacillus Calmette–Guérin (BCG) has been the standard of care treatment for non-muscle invasive bladder cancer (NMIBC) since the 1970s. Vaccination with BCG is known to induce durable functional and epigenetic reprogramming of myeloid cells to enhanced cytokine responses after secondary stimuli, a phenomenon known as “trained immunity” that contributes to long-term protection against respiratory infections other than tuberculosis. In a prospective observational cohort study that included 17 NMIBC patients, Jelmer H van Puffelen and colleagues show that intravesical BCG causes changes in ex vivo cytokine production as well as epigenetic and transcriptomic modifications in peripheral blood mononuclear cells (PBMCs), consistent with trained immunity. At 6 and 12 weeks after BCG instillation, production of IL-1beta and tumor necrosis factor (TNF) in PBMCs were significantly increased above pre-instillation levels. No significant epigenetic changes were detected in the promoter regions or gene bodies for the loci encoding IL-1beta, IL-6, or TNF. However, genes involved with IL-32, autophagy, and histone 3 lysine 9 (H3K9) methylation were differentially epigenetically modified after BCG instillation. An enrichment for interferon-responsive elements was also seen in the differentially expressed genes at the post-instillation versus pre-instillation time points. In a separate cohort including 407 BCG-treated and 250 non-BCG treated patients with NMIBC, risk of respiratory infections was reduced by 37% in the treated patients. These results reveal new insight into durable alterations in systemic immunity associated with local immunotherapy and may open new avenues of inquiry into mechanisms of resistance and response to treatment.

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SITC Members Receive 50 Percent Submission Discount in 2021

*As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC will provide members with a 50 percent discount on processing fees for all JITC articles accepted in 2021.