JITC Digest June 2025

By JITC Publications posted 26 days ago

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INSIDE THIS ISSUE:

Letter from the Editor | JITC Editor Picks | Updated Journal Metrics | Popular Archive Articles

Letter from the Editor

Hello JITC
Readers,

With the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting behind us, we can now look forward to getting our abstracts for the SITC meeting in the fall with the submission deadline coming up on June 26^th! The ASCO meeting, for me, was a wonderful time at the SITC booth to catch up with old friends from around the world, SITC staffers, and biotech and pharma companies working hard along with academics, supporting this Cancer Immunotherapy Month^TM. My “Meet-the-Editor” session at ASCO was also an opportunity to hear from some satisfied authors who commented on their comfort with the rapid and effective editorial process (which speaks to our truly amazing staff as well as Section and Associate Editors). Also, remarkable to me, was the sense of imminence and clarity about how important advances continue to be made in Immuno-Oncology (IO). This included the early Keynote at ASCO from my colleague at the University of Pittsburgh, Dario Vignali, focusing on the long road to make effective therapeutic antibodies to LAG3. Studies in the clinic of these and other IO agents, in turn, have led to much deeper understanding of the underlying complex biology. The interface between immune mechanisms and cancer development, as well as creating effective IO agents, speaks to our deepening understanding of the critical mechanisms that underly both the development of a cancer in an immunocompetent host but also the means to recover and enhance immunity.

Much of my recent thinking about this complex biology at the interface of these areas has to do with the concept of ‘oncogenes’, well-illustrated in selected papers in this month’s Digest. The molecular biology of these genes allowed us to initially understand the mechanisms for so-called driver mutations, central to the tumor process. Now in a more modern era, where IO agents are pillars of our therapeutic approaches to cancer patients, we should reflect on what appears to be a consistent finding of emergent immune responses when effective small molecules, now available, inhibit the individual oncogenes. A panoply of driver oncogenes including mutant BRAF, KRAS, Wnt/β-catenin, p38, ATRX, and others when inhibited effectively, lead to emergent immune responses that had been limited prior to treatment in patients. Thus, perhaps we need to reconsider this profound and emergent sense of the immunobiology of cancer. Indeed, there appears to be an extraordinarily early immune component woven into emergence of tumors with most effective oncogenes suppressing immunity. Stay tuned for more about this in JITC as we explore this space, inviting original articles to further investigate the intersection of cancer biology and immunity.

Regards,

Michael T. Lotze, MD
Editor-in-Chief
Journal for ImmunoTherapy of Cancer

JITC Editor Picks

B4GALT5 inhibits CD8⁺ T-cell response by downregulating MHC-I level through ERAD pathway in PDAC

Summary:

The notion that pancreatic cancer occurred in an immunosuppressive environment driven by vagal efferents as well as autophagy-limiting expression of class I expression had been well-established in the field. Here, overexpression of beta-1,4-galactosyltransferase-5 (B4GALT5) was shown to also inhibit class I expression by promoting ubiquitination and degradation within the proteosome. Furthermore, by knocking down expression, the authors enhanced T cell infiltration and CD8⁺activation with expression of granzyme and effector cytokines. Examination of The Cancer Genome Atlas database revealed that expression of B4GALT5 negatively correlated with T cell infiltrate in patients with pancreatic cancer. Prior studies have defined this glycosylation regulator as a glyco-oncogene and one of several glyco-tumor suppressor genes important in human hepatocellular and ovarian cancer. This molecule thus appears to be part of a promising pathway for further evaluation and targeting in patients with pancreatic ductal adenocarcinoma.

Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy

Summary:

Consistent with the theme for this month of the intersection of oncogenes and immunobiology, loss of genes that regulate necroptosis, such as mixed lineage kinase domain-like pseudokinase (MLKL) and receptor interacting protein kinase 3 (RIPK3), have been shown to be driven by the BRAF and AXL oncogenes. Death used to be much simpler! We previously understood normal programmed cell death or apoptosis and distinguished it from passive cell death or necrosis. Now necroptosis, ferroptosis, alkaliptosis, pyroptosis, and other pathways have been identified as important alternative means of programmed cell death (and distinguished from programmed cell survival or autophagy). Here, the authors showed in murine tumor models that ablation of MLKL or RIPK3, limiting necroptosis, also decreased immune reactivity and elimination of tumors. Responsiveness to immune checkpoint blockade (ICB) was severely limited, unlike the wild-type tumors. Furthermore, melanoma patients with high expression of MLKL had better overall survival and durable clinical response to ICB. Enhancing necroptosis in patients with cancer thus represents an important novel pathway for advancing effective therapeutics.

Sensitivity to immune checkpoint inhibitors in BRAF/MEK inhibitor refractory melanoma

Summary:

Oncogenic activation of BRAF/MEK through mutation has been known to be associated with local immunosuppression within the tumor. Furthermore, we have known that BRAF/MEK inhibition can in turn lead to subsequent release from such immunosuppression, associated with increased T cell infiltrate. Still, acquired resistance to BRAFi and MEKi inhibitors in melanoma occurs in most patients, often due to MAPK/ERK pathway reactivation. Here, the authors show that hyperactivation of the epidermal growth factor receptor (EGFR), with STAT3 and STAT5 phosphorylation, is observed in patients with secondary resistance to BRAFi/MEKi but who are still responsive to ICB. This was initially observed in mouse models where BRAF/MEK-resistant tumors were susceptible to ICB in immunocompetent but not in NSG mice. We now could identify those patients who might be most likely to respond to ICB following acquired resistance to BRAFi/MEKi.

Tumor-secreted galectin-3 suppresses antitumor response by inducing IL-10⁺ B cells

Summary:

Gal3 (LGALS3) is not an oncogene but rather supportive of oncogenic RAS pathways, promoting the stability of BCL2 family members as well as enhancing the proliferative pathways associated with the Wnt/β-catenin pathway. Here, the authors show that Gal3, frequently expressed on several tumors, but here studied in patients with breast cancer, interacted with CD45 on B cells to upregulate and drive so called Bregs, capable of producing IL-10. Such B10 cells, on interaction with T cells, limited immune reactivity to tumor. Available Gal3 inhibitors, already tested in the clinic, could thus be coupled with other forms of chemotherapy in breast cancer to limit immunosuppression mediated by such B10 cells.

Updated Journal Metrics

As journals everywhere take time to update readers on their journal metrics this month, JITC is pleased to share a variety of quality metrics that demonstrate the journal’s strength in publishing IO research that spans from bench to bedside. View the latest metrics.

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