JITC Digest January 2024

By JITC Publications posted 01-17-2024 15:52

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Inside this Issue:

Letter from the Editor JITC Editor Picks Thank You to JITC Reviewers Popular Archive Articles

Letter from the Editor

Hello JITC Readers,

Welcome to the first JITC Digest of 2024. I hope everyone had the chance to relax around the turn of the year and spend time with family, friends, and loved ones. With a new year comes optimism and the prospects of exciting times ahead.

In the meantime, I would like to call your attention to some outstanding research recently published in the journal. Highlights this month include an article from Wenhao Xu et al in which they used immunohistochemistry and multispectral fluorescence to evaluate tertiary lymphoid structure (TLS) heterogeneity and tumor microenvironment cell-infiltrating characterizations in patients with clear cell renal cell carcinoma (ccRCC). Their findings show the impact that TLS localization and maturation have on clinical outcomes of ccRCC, potentially serving as a prognostic indicator.

In a fascinating study, Manali S. Phadke and colleagues address the question of whether there is mechanistic overlap of anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combination treatments in advanced melanoma. Utilizing a high throughput analysis in combination with protein assays, their results demonstrate that patients who have resistance to one of the two immune checkpoint inhibitor combinations may respond to the other option, suggesting that second line immunotherapy with a different mechanism of action could elicit a favorable response. Be sure to check out these selections and more below in the Editor Picks.

Lastly, I would like to send my sincerest thanks to the nearly 1,500 individuals who reviewed for JITC in 2023. We could not maintain the high standards and continue to publish such quality work without the generous efforts of our reviewers. For more information on the benefits of reviewing for JITC or to volunteer for the role, please see the special feature below for more information.

Looking forward to the year ahead!

Regards,

James L. Gulley, MD, PhD, FACP

Journal for ImmunoTherapy of Cancer Interim Editor-in-Chief

JITC Editor Picks

Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma

Wenhao Xu, Jiahe Lu, Wang-Rui Liu, Aihetaimujiang Anwaier, Yuhao Wu, Xi Tian, Jia-Qi Su, Yuan-Yuan Qu, Jianfeng Yang, Hailiang Zhang, Dingwei Ye
Journal for ImmunoTherapy of Cancer 2023;11:e006667 (1 December 2023)
RESEARCH

Summary:

Clear cell renal cell carcinoma (ccRCC) accounts for over 76% of adult kidney cancers. As such, it is important to identify prognostic indicators to improve the management of ccRCC. Tertiary lymphoid structures (TLS) have been shown to play a role in facilitating immune cell infiltration into the tumor microenvironment (TME). Using immunohistochemistry and multispectral fluorescence on the TLS of patients with ccRCC, the investigators found both tumor proximal and distal TLS in 34.2% of ccRCC samples. Interestingly, tumor proximal TLS were more mature than distal TLS and were significantly correlated to improved progression-free survival and overall survival. Further, maturity of TLS was also significantly associated with better clinical outcomes. These data demonstrate the impact of TLS localization and maturation on the clinical outcomes of ccRCC, which could serve as a prognostic indicator.

Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models

Manali S Phadke, Jiannong Li, Zhihua Chen, Paulo C Rodriguez, Jessica K Mandula, Lilit Karapetyan, Peter A Forsyth, Y Ann Chen, Keiran S M Smalley
Journal for ImmunoTherapy of Cancer 2023;11:e007239 (6 December 2023)
RESEARCH

Summary:

The two combination treatments of anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 have demonstrated good efficacy for the treatment of advanced melanoma. However, it is unclear whether there is a mechanistic overlap of these treatment options. To address this question a high throughput analysis in combination with protein assays were used. Analysis of T cell subsets showed that combination anti-PD-1+CTLA-4 therapy drove a more regulatory T cell response, whereas anti-PD-1+LAG-3 therapy demonstrated a T helper 2 T cell response, with the anti-PD-1+LAG3 response being dependent on CD4⁺T cells. These data demonstrate that the two clinically relevant immune checkpoint inhibitor combinations have unique effects on the polarization of CD4⁺T cell and subsequent cytotoxic CD8⁺T cell function and have implications that patients who demonstrate resistance to one combination therapy could still respond to second option.

Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study

Dominik A Barth, Florian Moik, Sarah Steinlechner, Florian Posch, Marie-Christina Mayer, Amelie M Sandner, Franziska Berton, Verena Schlintl, Lukas Koch, Nikolaus John, Robert Wurm, Martin Pichler, Thomas Bauernhofer, Patrick Reimann, Christoph Wohlkönig, Erika Richtig, Thomas Winder, Matthias Preusser, Philipp J Jost, Cihan Ay, Armin Gerger, Angelika Terbuch, Jakob Michael Riedl
Journal for ImmunoTherapy of Cancer 2023;11:e007765 (14 December 2023)
RESEARCH

Summary:

C-reactive protein (CRP) kinetics have been associated with treatment efficacy and disease progression in select cancer types in the past. However, many studies have not treated CRP as the time-dependent variable that it is. This study examined CRP kinetics following ICI therapy across a variety of cancer types in 1,036 patients and identified four CRP groups: all-normal CRP, CRP responders, CRP flare-responders, and CRP non-responders. Using multivariable analysis, they demonstrated that CRP response kinetics were predictive for treatment efficacy, with overall survival and progression-free survival being highest in the all-normal CRP and lowest in the CRP non-responders. These data suggest that CRP kinetics analysis could be a cost-effective way to assess early treatment response and could be used to identify early primary treatment resistance and rapid disease progression.

Scalable generation of functional human iPSC-derived CAR-macrophages that efficiently eradicate CD19-positive leukemia

Shifaa M. Abdin, Daniela Paasch, Arnold Kloos, Marco Carvalho Oliveira, Mi-Sun Jang, Mania Ackermann, Andriana Stamopoulou, Philipp J Mroch, Christine S Falk, Constantin S von Kaisenberg, Axel Schambach, Michael Heuser, Thomas Moritz, Gesine Hansen, Michael Morgan, Nico Lachmann
Journal for ImmunoTherapy of Cancer 2023;11:e007705 (22 December 2023)
RESEARCH

Summary:

The purpose of this study was to establish a more efficient method of CAR-macrophage generation that is conducive to upscaling production for treatment. The investigators used genetic engineering to derive CD19-targeting human CAR-macrophages from induced pluripotent stem cells (iPSC). The iPSC-derived CAR-macrophages showed efficacy in CD19⁺cancer cell lines and patient-derived acute lymphocytic leukemia cancer cells ex vivo, all in a CD19 expression-dependent manner. Further analysis of the iPSC-derived CAR-macrophages via single-cell RNA sequencing revealed that they were distinct from enhanced green fluorescent protein control cells under identical conditions, indicating that these CAR-macrophages could produce a pro-inflammatory state in response to CD19⁺cancer cells. In summary, this novel CAR-macrophage generation method overcomes the issue of potential insufficient monocyte recovery from donors and the time- and cost-intensive problems of traditional CAR-macrophage generation.

**Other Recent JITC Articles**

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**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 15% discount on the article processing charges (APC) for accepted papers on which they are authors in 2024.

If you would like to support the journal while also gaining the many benefits of being a peer reviewer, we welcome applications, which may be submitted through the SITC Volunteer Portal.

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