JITC Digest December 2024

By JITC Publications posted 12-18-2024 10:06

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INSIDE THIS ISSUE:

Letter from the Editor | JITC Editor Picks | JITC Social Media | Popular Archive Articles

Letter from the Editor

Hello JITC Readers,

Welcome to the latest JITC Digest, our final edition of 2024 in my ‘dragon year’. The end of each year can serve as a time of reflection, and as I look back over these last twelve months, a feeling of gratitude and excitement for our field is one that I will associate with my first year as JITC Editor-in-Chief. It has been an honor to take over this prestigious position, and I have been nothing but impressed by so many aspects of the role and everyone with whom I have had the pleasure of getting to know. This of course includes precious time that I got to spend with both Pedro Romero, our Founding Editor-in-Chief, as well as our Interim Chief, James Gulley.

A successful journal is the result of countless individuals working in concert to produce the best possible manuscripts, and I have been astounded by the dedication of our editorial board members, the diligence and sheer number of volunteer reviewers, the remarkable abilities of our JITC staff and supports from our publishers at BMJ, and the incredible amount of quality research done by our authors across the globe. While I am grateful for this opportunity to lead JITC, I am equally excited for the year ahead and what the journal has in store.

Some of that quality research can be found in this month’s highlights, including findings from a well-controlled study described by Delaney Ramirez et al, investigating the relationship between depletion of specific CD4⁺immune cell subpopulations and the associated impact on CD8⁺T cell response. Using mouse models, CD4 depletion was found to promote greater tumor antigen-specific CD8⁺T-cell priming, dissemination, and formation of memory cells than dual immune checkpoint blockade. Importantly, this was found to not be driven by homeostatic proliferation or depletion of CD4⁺dendritic cells, but rather by ablation of both T regulatory cells as well as CD4⁺Foxp3^-conventional T cells. This has potential important clinical implications that could unleash the capabilities of tumor-controlling CD8⁺T cells.

Additionally, Amaia Martinez-Usatorre and colleagues identified 226 RNA biomarkers from peripheral blood mononuclear cells (PBMC) using transcriptomic analysis that uncovered stage-specific modifications to immune activity in patients with various stages of colorectal cancer (CRC), including precancerous disease. Early CRC stages showed innate immune activation, including myeloid cell involvement, while later stages involved T-cell suppression, exuberant wound healing, and platelet activation, with these changes mirroring key processes in CRC pathophysiology. Thus, the PBMC could harbor important information that we could discern with the help of these advanced strategies helping us to better understand the tumor-immune interface without having to repetitively biopsy the tumor.

Wishing you all a wonderful holiday season and best wishes in the year ahead! We will be revealing multiple new strategies to help advance the field of Cancer Immunotherapy in JITC with a new appearance to our articles, commentaries from worldwide experts in the field helping us celebrate SITC’s 40^th anniversary, and more. Stay tuned!

Regards,

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

JITC Editor Picks

Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy

Delaney E Ramirez, Christo P C Dragnev, Tyler G Searles, Nathaniel Spicer, Tiffany Chen, J Louise Lines, Aaron R Hawkes, Wilson L Davis, Asmaa Mohamed, Keisuke Shirai, Joseph D Phillips, Pamela C Rosato, Yina H Huang, Mary Jo Turk
Journal for ImmunoTherapy of Cancer 2024;12:e010170 (9 November 2024)
RESEARCH

Summary:

CD4 depletion therapy using anti-CD4 antibodies has shown anti-tumor activity both preclinically and clinically. However, the mechanism that drives this efficacy is not well understood. This study analyzed mouse models inoculated with B16-F10 melanoma cells with single cell RNA sequencing to uncover the relationship between depletion of specific CD4⁺ immune cell subpopulations and the associated impact on CD8⁺ T cell priming, dissemination, and immune response. Results indicated that CD4 depletion resulted in greater tumor antigen (Ag)-specific CD8⁺ T cell priming, dissemination, and formation of memory cells than dual immune checkpoint blockade. However, this phenomenon was not driven by homeostatic proliferation or depletion of CD4⁺ dendritic cells (DCs), but rather complete ablation of both T regulatory cells as well as, surprisingly, CD4⁺ Foxp3^-conventional T (Tconv) cells. Pivotal to the mechanism of anti-CD4 treatment efficacy, depletion of Tconv cells was shown to drive the accumulation and maturation of conventional type-1 DCs within the tumor draining lymph nodes, a requirement for CD8⁺ T cell priming. These results highlight the important role of CD4⁺ Tconv depletion in promoting systemic primary and memory CD8⁺ T cell responses.

Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression

Malte Roerden, Andrea B Castro, Yufei Cui, Noora Harake, Byungji Kim, Jonathan Dye, Laura Maiorino, Forest M White, Darrell J Irvine, Kevin Litchfield, Stefani Spranger
Journal for ImmunoTherapy of Cancer 2024;12:e010249 (9 November 2024)
RESEARCH

Summary:

High intratumoral heterogeneity and subclonal neoantigen (NeoAg) expression have been shown to dampen anti-tumor T-cell responses and are associated with poor outcomes to immune checkpoint blockade (ICB), however, the mechanism that drives the disruption of the T-cell response is yet to be fully understood. This study investigated how the NeoAg architectures influence tumor immunogenicity and immune evasion using various mouse models with lung adenocarcinoma and controlled expression of both clonal as well as subclonal NeoAgs. Tumors with uniform clonal NeoAg expression had higher immunogenicity (evidenced by greater IFN-γ secretion), while heterogeneous NeoAg expression suppressed immune responses, a phenomenon driven by cross-presenting dendritic cells (cDC1). cDC1 cells in the lymph nodes were shown to reflect tumor NeoAg expression, leading to mutually beneficial response in tumors with clonal NeoAg expression and competition between T cell responses in heterogeneous tumors that resulted in resistance to ICB. Therapeutic RNA-based vaccines targeting suppressed NeoAgs, combined with ICB, reactivated the T cell response and enhanced tumor control in mouse models. These insights emphasize DCs as critical mediators of NeoAg-dependent antitumor immunity and underscore the need for personalized immunotherapy strategies tailored to the clonality/heterogeneity of the tumor.

Human blood cell transcriptomics unveils dynamic systemic immune modulation along colorectal cancer progression

Amaia Martinez-Usatorre, Laura Ciarloni, Paolo Angelino, Victoria Wosika, Alessandra Jordano Conforte, Sara S Fonseca Costa, Eric Durandau, Sylvain Monnier-Benoit, Hector Fabio Satizabal, Jérémie Despraz, Andres Perez-Uribe, Mauro Delorenzi, Stephan Morgenthaler, Brian Hashemi, Noushin Hadadi, Sahar Hosseinian-Ehrensberger, Pedro J Romero
Journal for ImmunoTherapy of Cancer 2024;12:e009888 (21 November 2024)
RESEARCH

Summary:

Emerging screening tools to detect early development of colorectal cancer (CRC), such as measurement of circulating tumor DNA (ctDNA), have insufficient sensitivity to identify precancerous disease, requiring better methods for early detection. This study used whole transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) from patients with CRC, those with only precancerous lesions, or normal individuals with negative colonoscopy results to investigate systemic immune modulation and identify biomarkers related to early disease progression. A total of 226 RNA biomarkers were identified that uncovered stage-specific changes to immune activity to the colonic epithelium. Early CRC stages featured activation of innate immunity, including enhanced reactive oxygen species metabolic pathways mediated by myeloid cells. These early stages were also characterized by upregulation of B-cell activation genes and markers of myeloid cell activation/migration. Progression into later stages of CRC revealed upregulated transcriptomes within the PBMCs, related to inflammation, wound healing, and coagulation. Key pathways included platelet activation and neutrophil-driven immune responses, aligning with known CRC pathophysiology and the emergence of neutrophil/lymphocyte ratios as prognostic mediators. This study provides strong transcriptomic evidence of early and detectable immune modulation in the periphery of patients with various stages of CRC, including precancerous disease, that may be useful as biomarkers for noninvasive early detection as well as predictive and/or prognostic biomarkers with treatment.

Degradation of PARP1 by MARCHF3 in tumor cells triggers cCAS-STING activation in dendritic cells to regulate antitumor immunity in hepatocellular carcinoma

Jun Cao, Bingbing Su, Chi Zhang, Rui Peng, Daoyuan Tu, Qiangwei Deng, Guoqing Jiang, Shengjie Jin, Qian Wang, Dou-Sheng Bai
Journal for ImmunoTherapy of Cancer 2024;12:e010157 (27 November 2024)
RESEARCH

Summary:

The role of membrane-associated ring-CH-type-finger 3 (MARCHF3) in the development of immune responses following immune checkpoint inhibitor (ICI) treatment is not well-defined.
This study sought to uncover mechanistic drivers of response to ICI related to MARCHF3 involvement in patients with hepatocellular carcinoma (HCC). Using immunohistochemistry and transcriptomic analysis of human HCC tissues samples, along with in vivo mouse models (C57BL/6J mice with Hepa1-6 tumor cells), MARCHF3 was shown to promote the ubiquitination and degradation of Poly (ADP-Ribose) Polymerase 1 (PARP1), a DNA repair protein, leading to accumulation of cytosolic double-stranded DNA. This subsequently triggered the cGAS-STING pathway in dendritic cells (DCs), promoting antigen presentation and CD8⁺T cell activation. Higher MARCHF3 expression was associated with enhanced immune cell infiltration and response to ICIs. Overexpression of MARCHF3 in mice sensitized the tumors to treatment, while its absence impaired responses. This study highlights the significant role of MARCHF3 as a potential biomarker for immunotherapy sensitivity and as a critical regulator of antitumor immunity in HCC, directly interacting with PARP1 and promoting antigen presentation.

JITC Social Media

Stay informed on all that is happening at JITC by following on LinkedIn, X, and WeChat. In addition to sharing the latest publications, JITC’s social media accounts also provide deeper dives into recently published articles, early career author spotlights, and additional conference coverage of select meetings. You can also see what our editors find of particular interest through Editor-in-Chief selections of recent JITC highlights as well as the monthly Reading List that calls attention to key publications across the immuno-oncology field. Keep up to date by following JITC on social media!

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