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Letter from the Editor

Hello JITC Readers,

I welcome you not only to the February JITC Digest, but to the Year of the Snake as well. While symbolically representing wisdom and intelligence, the serpent also calls to mind the Rod of Asclepius and serves as an important reminder of our important roles in the field of medicine. That includes the nearly 1,400 individuals who reviewed for JITC in 2024. I send them my sincere gratitude for their tireless efforts to ensure that each paper published in our journal supports the advancement of IO with rigorous science and clinical application. If you would like to learn more about the benefits of reviewing for JITC or volunteer for the role, please see the special feature below.

Additionally, seeing as the number two is considered good luck in the Year of the Snake, I am pleased to announce the final publications for two articles of JITC’s highly-accessed special series: “Cancer Immunotherapy in Understudied Populations” and “Computational I-O.” The former addresses immunotherapy treatments and immune response among understudied populations with respect to age, race, ethnicity, and social determinants. The latter provides perspectives – past, present, and future – on the role of computational science in the field of immuno-oncology. I encourage you to check out the special feature below to learn more about these two fascinating new collections.

In addition to the review articles that conclude these special series, there were several other notable works recently published in JITC. Highlights for this month include exciting preclinical data from Ryan Kowash and colleagues on a potential therapeutic target for solid tumors identified in a non-small cell lung cancer model. This group engineered a monoclonal antibody (AHA-1031) to target major histocompatibility complex class I-related chain A or B (MICA/B), to be used to both inhibit MICA/B shedding and enhance antibody-dependent cellular cytotoxicity killing by natural killer cells. The antitumor activity demonstrated by AHA-1031 in this study indicates a possible alternative treatment strategy for tumors, particularly those with KRAS mutations that do not respond well to immunotherapies.

Additionally, Anton Lahusen et al used an unbiased screening approach to identify a novel protein, transglutaminase 2 (TGM2), as a driver of T cell suppression in pancreatic ductal adenocarcinoma (PDAC). TGM2 expression in patient tumors was also correlated with an immunosuppressive signature and poor overall survival. Their validation of TGM2 as an immunosuppressive protein in PDAC provides an exciting potential therapeutic target to improve treatment of PDAC.

Don’t miss these highlights and more in the latest Digest.

Regards,

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

JITC Editor Picks

Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models

Ryan Kowash Manoj Sabnani Ryan R Kowash, Manoj Sabnani, Laura T Gray, Qing Deng, Nusrat U A Saleh, Luc Girard, Yujiro Naito, Kentaro Masahiro, John D Minna, David E Gerber, Shohei Koyama, Zhiqian Lucy Liu, Hemanta Baruah, Esra A Akbay Journal for ImmunoTherapy of Cancer 2025;13:e009867 (6 January 2025) RESEARCH Summary: Non-small cell lung cancers (NSCLC) that contain KRAS LKB1 (STK11, KL) mutations are difficult to treat since they do not respond well to immune checkpoint blockade therapies. NSCLC cell lines exhibit high cell surface expression and secretion of major histocompatibility complex class I-related chain A or B (MICA/B), a well-known target for the identification and clearance by natural killer group 2D (NKG2D)-expressing cells. The investigators engineered a monoclonal antibody (AHA-1031) that targets MICA/B. Analysis of NSCLC cell lines via ELISA and flow cytometry showed that AHA-1031 was bound to MICA/B and inhibited ligand shedding without interfering with cell binding to NKG2D+ NK cells. When analyzed in three KL mutant xenograft/PDX models, AHA-1031 significantly inhibited tumor growth compared to vehicle-treated controls. These findings demonstrate a promising alternative therapy strategy to target KL tumors and has broad implications for MICA/B expressing tumors.

XCL1-secreting CEA CAR-T cells enhance endogenous CD8+ T cell responses to tumor neoantigens to confer a long-term antitumor immunity

Chunfeng Qu Xing-Ning Li, Feifei Wang, Kun Chen, Zhiyuan Wu, Ruochan Zhang, Chentong Xiao, Fei Zhao, Dongmei Wang, Hong Zhao, Yuliang Ran, Chunfeng Qu Journal for ImmunoTherapy of Cancer 2025;13:e010581 (6 January 2025) RESEARCH Summary: The carcinoembryonic antigen (CEA)-specific chimeric antigen receptor (CAR) as a therapeutic option is limited in efficacy against colorectal cancer (CRC) due to unique microenvironments of tumors. A conventional CEA-CAR (reg-CAR) construct was modified to express XCL1 and interleukin (IL)-7 genes, resulting in a modified 7XCL1-CAR.  The goal was to stimulate endogenous CD8+ T cell responses to neoantigens and limit persistent tumor resistance. A 60-hour co-culture of CAR T cells with CEA-expressing CRC cells revealed higher cytotoxicity in 7XCL1-CAR T cells than in reg-CAR T cells. This enhanced cytotoxicity was mediated by higher secretion of XCL1 and IL-7 in 7XCL1-CAR T cells, which effectively recruited type 1 conventional dendritic cells (cDC1s) to sustain antitumor activity. A similar trend occurred in tumor-bearing mouse models with heterogenous CEA expression. Additionally, following 7XCL1-CAR T cell treatment, mice demonstrated resistance to challenge with CEA-negative CT26 cells, indicating endogenous neoantigen-specific T cell expansion and long-term antitumor immunity.

Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines

Anton Lahusen Anton Lahusen, Nora Minhöfer, Kim-André Lohse, Christine Blechner, Jessica Lindenmayer, Tim Eiseler, Anton Wellstein, Alexander Kleger, Thomas Seufferlein, Sabine Windhorst, Yuan-Na Lin Journal for ImmunoTherapy of Cancer 2025;13:e010579 (16 January 2025) RESEARCH Summary: Pancreatic ductal adenocarcinoma (PDAC) is described as a “cold” tumor type due to the immunosuppressive environment and poor T cell infiltration, and is often refractory to immunotherapies as a result. The investigators sought to identify targetable factors that promote the immunosuppressive environment. An unbiased 3D transcriptomic screening approach on a co-culture of murine PDAC cells and syngeneic antigen-educated T cells identified potential cell-intrinsic drivers of T cell suppression in PDAC. Validation studies confirmed that transglutaminase 2 (TGM2) is a driver of T cell suppression in PDAC by altering the microtubule dynamics and vesicle trafficking to facilitate the secretion of immunosuppressive cytokines. High TGM2 expression in patient tumors were also correlated with immunosuppressive signatures and poor overall survival. Inhibition of TGM2 through a variety of mechanisms increased T cell-mediated apoptosis of PDAC cells, indicating that targeting of TGM2 processes therapeutically may enhance antitumor responses in the treatment of PDAC.

Divergent transcriptional states and kinetics of circulating tumor-infiltrating lymphocyte repertoires with highly homologous T-cell receptor sequences in a patient during immunotherapy

Ryutaro Kajihara Mark D Long Ryutaro Kajihara, Mark D Long, Toshifumi Hoki, Hongbin Chen, Takayoshi Yamauchi, Hisashi Kanemaru, Brahm H Segal, Grace K Dy, Fumito Ito Journal for ImmunoTherapy of Cancer 2025;13:e010092 (25 January 2025) SHORT REPORT Summary: Evidence has shown that some T-cell receptors (TCRs) that recognize the same epitopes actually have slightly different TCR sequences. This report examined the evolution of features in circulating TCR clonotypes observed in tumors (tumor-infiltrating lymphocyte (TIL)-TCRs) by combining single-cell RNA/TCR sequencing of longitudinal blood samples and TCR sequencing of tumor tissue from a patient treated with anti-CTLA-4/PD-1 therapy. They found frequent circulating CD8+ TIL-TCRs with identical CDR3α sequences but quasi-identical CDR3β and TCR α/β sequences. These homologous TIL-TCRs responded differently to immunotherapy and exhibited distinct transcriptional signatures as distinguished by GZMK expression. Overall, CD8+ TIL-TCRs demonstrated an increase in expression of IFNG when the patient achieved a response and a subsequent reduction in expression as the patient acquired resistance to treatment. These findings highlight that CD8+ T cells with highly homologous TCR sequences display divergent transcriptional states and kinetics in response to immunotherapy.

Thank You To JITC Reviewers

JITC sends a heartfelt thank you to the many peer reviewers whose role in evaluating manuscripts is essential to maintaining the high standards of quality of publications in the journal and in helping JITC continue to thrive. As another way to thank these indispensable colleagues, JITC reviewers who have completed reviews in the past 12 months are eligible for a 10% discount on the article processing charges (APC) for accepted papers on which they are first, last, or corresponding authors in 2025.       If you would like to support the journal while also gaining the many benefits of being a peer reviewer, we welcome applications through the SITC Volunteer Portal.

Two Complete Special Series:
Cancer Immunotherapy in Understudied Populations & Computational I-O

Popular Archive Articles