JITC Digest January 2022

By JITC Publications posted 01-19-2022 00:00

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INSIDE THIS ISSUE:

LETTER FROM THE EDITOR JITC EDITOR PICKS

Letter from the Editor

Dear JITC Readers,

Welcome to the New Year and one that happens to be of great significance to the journal, as JITC will celebrate its 10^th anniversary in 2022. It is humbling to look back on how far JITC has come in the past 10 years, and we are all excited for what the future holds.

Of course, it is the top-caliber articles published in JITC that have supported the journal’s ascent to being among the most highly-ranked oncology and immunology journals. This past year was no exception, and we are highlighting some of the top-most accessed and downloaded articles from 2021 in this month’s special feature.

The original research spotlighted in this month’s digest offers new insights on a diverse array of emerging areas in the immunotherapy field.

Jinzhu Mao and colleagues offer a detailed metagenomic census of the gut microbiome in patients with hepatobiliary cancers being treated with immunotherapy, showing that the presence of many lower-level taxa is not “one-size-fits-all” for clinical benefit.

A novel feedback loop involving CCL18-mediated crosstalk between tumor-associated macrophages and ovarian carcinoma cells promoting epithelial-to-mesenchymal transition and other invasive characteristics is described by Lingli Long et al.

Sub-cytotoxic doses of a metabolite of the topoisomerase I inhibitor irinotecan were demonstrated to enhance responses to anti-PD-1 via activation of FOXO3 and enhanced tumor infiltration of natural killer cells by Young Min Chung and colleagues.

Finally, Giuseppe Minniti et al present the results of a retrospective study indicating that the addition of immunotherapy to postoperative stereotactic radiosurgery reduces the risk of leptomeningeal disease for patients with melanoma and non-small cell lung cancer brain metastases.

Looking forward to what is in store for 2022!

Best,

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

**Other Recent JITC Articles**

In Memoriam: Martin A. "Mac" Cheever

Martin A. “Mac” Cheever, MD, passed away in September 2021 at the age of 77. A pioneer in immuno-oncology, Dr. Cheever dedicated his life to immunotherapies throughout a distinguished and groundbreaking career. While he is deeply missed by family, friends, colleagues, and the countless lives he touched, his life’s work will continue to shape the I-O landscape for years to come. Read the tribute honoring Dr. Cheever (1944–2021).

JITC Editor Picks

GUT MICROBIOME IS ASSOCIATED WITH THE CLINICAL RESPONSE TO ANTI-PD-1 BASED IMMUNOTHERAPY IN HEPATOBILIARY CANCERS

Jinzhu Mao, Dongxu Wang, Junyu Long, Xu Yang, Jianzhen Lin, Yiwei Song, Fucun Xie, Ziyu Xun, Yanyu Wang, Yunchao Wang, Yiran Li, Huishan Sun, Jingnan Xue, Yang Song, Bangyou Zuo, Junwei Zhang, Jin Bian, Ting Zhang, Xiaobo Yang, Lei Zhang, Xinting Sang, Haitao Zhao
Journal for ImmunoTherapy of Cancer 2021;9:e003334 (6 December 2021)
Research

Summary:

The composition and diversity of the gut microbiota has been linked to clinical outcomes for patients receiving checkpoint blockade for multiple solid tumors. Metagenomic sequencing of pre- and on-treatment stool samples from 65 patients with advanced hepatobiliary cancers by Jinzhu Mao et al describe the first set of specific taxa and functional genomic signatures associated with clinical benefit and toxicity for patients with hepatobiliary cancers receiving second-line checkpoint blockade therapy. At the phylum level, a statistically significantly higher abundance of Bacteroidetes was observed in the group that derived clinical benefit. Among the group with disease that did not respond to checkpoint blockade, the most predominant taxa belonged to the Proteobacteria phylum. No significant difference was found in alpha diversity between the group that benefited and those that did not. Stratifying by species, higher abundance of the butyrate-producing Lachnospiraceae bacterium-GAM79 was associated with longer progression-free survival (PFS) and overall survival (OS). Poor PFS and OS outcomes were observed for patients with high abundances of the Veillonellaceae family. Clinically severe diarrhea was associated with better response to anti-PD-1 as well as lower phylogenetic diversity in the composition of the gut microbiota and enrichment for members of the Firmicutes phylum. Functional genome annotation revealed enrichment for pathways involved in aurachin metabolism, fatty acid biosynthesis, acarbose biosynthesis, and polyketide sugar unit biosynthesis linked with clinical benefit. The findings highlight the diversity of potential impacts of the gut microbiota on response to immunotherapy across different cancers.

TUMOR-ASSOCIATED MACROPHAGES INDUCED SPHEROID FORMATION BY CCL18-ZEB1-M-CSF FEEDBACK LOOP TO PROMOTE TRANSCOELOMIC METASTASIS OF OVARIAN CANCER

Lingli Long, Yue Hu, Tengfei Long, Xiaofang Lu, Ying Tuo, Yubing Li, Zunfu Ke
Journal for ImmunoTherapy of Cancer 2021;9:e003973 (27 December 2021)

Research

Summary:

Tumor-associated macrophages (TAMs) are known to be abundantly present within ascites from patients with highly malignant ovarian carcinoma. Lingli Long and colleagues identify a positive feedback loop involving CCL18 secretion by M2-polarized TAMs leading to increased ZEB1 and other epithelial-to-mesenchymal transition (EMT) transcription factors expression in ovarian carcinoma cells that further enhances production of macrophage colony-stimulating factor (M-CSF). A newly established three-dimensional co-culture system, including ID-8 ovarian carcinoma cells and TAMs, showed enhanced migratory and invasive capacity, spindle morphology, expression of mesenchymal markers, and M-CSF production in tumor cells grown in spheroids. TAMs grown in spheroids had augmented M2 functionality, as measured by high expression of IL-10 and transforming growth factor beta, along with low IL-6 and tumor necrosis factor alpha. TAMs grown in spheroids were elevated for CCL18 at the transcript and protein level. Inhibition of the CCL18—CCR8 interaction in ovarian cancer cells attenuated EMT and M-CSF production. Immunoprecipitation showed binding of the EMT transcription factor ZEB1 at M-CSF promoters in tumor cells grown in spheroids. Overexpression of ZEB1 in tumor cells led to large, compact spheroids with centrally located TAMs—features associated with high dispersion potential and recapitulated in ascites isolated from human patients with high malignancy disease. In murine models, overexpression of ZEB1 in ovarian carcinoma cells was associated with short survival and severe metastatic symptoms.

SENSITIZING TUMORS TO ANTI-PD-1 THERAPY BY PROMOTING NK AND CD8+ T CELLS VIA PHARMACOLOGICAL ACTIVATION OF FOXO3

Young Min Chung, Pragya P Khan, Hong Wang, Wen-Bin Tsai, Yanli Qiao, Bo Yu, James W Larrick, Mickey C-T Hu
Journal for ImmunoTherapy of Cancer 2021;9:e002772 (9 December 2021)
Research

Summary:

Building on a serendipitous discovery that sub-cytotoxic doses of the irinotecan metabolite SN-38 suppress tumor growth in mouse models, Young Min Chung and colleagues demonstrate that low-dose SN-38 potentiates natural killer (NK) cell infiltration into the tumor microenvironment (TME) to enhance responses to anti-PD-1. In two syngeneic ovarian cancer mouse models, low-dose SN-38 administration improved survival and was associated with reduced PD-L1 expression on tumors cells, with a concomitant increase in nuclear FOXO3 expression. The combination of low-dose SN-38 and anti-PD-1 was associated with longer survival compared to either monotherapy in the syngeneic ID-8 model of ovarian carcinoma. Prolonged survival with low-dose SN-38, either alone or in combination with anti-PD-1, was also associated with enhanced intratumoral infiltration of NK cells, significantly higher numbers of apoptotic tumor cells, and increased detection of interferon gamma and granzyme B in the TME. Enhanced tumor cell killing by NK cells with low-dose SN-38 treatment was confirmed in vitro. Treatment with SN-38 and anti-PD-1 as well as the combined regimen led to reduced expression of the downstream targets of FOXO3 in vivo by immunohistochemistry and immunoblotting, specifically STAT3 and c-Myc. In vitro, silencing of FOXO3 eliminated the downregulation of PD-L1 expression observed with low-dose SN-38 in two cell lines, and enforced overexpression of FOXO3 led to reduced PD-L1 expression in the absence of drug treatment. Data from human patients supported the mechanisms put forward in pre-clinical models, demonstrating that expression of PD-L1 protein was strongly associated with c-Myc levels in ovarian carcinoma, invasive breast carcinoma, and hepatocellular carcinoma.

LEPTOMENINGEAL DISEASE AND BRAIN CONTROL AFTER POSTOPERATIVE STEREOTACTIC RADIOSURGERY WITH OR WITHOUT IMMUNOTHERAPY FOR RESECTED BRAIN METASTASES

Giuseppe Minniti, Gaetano Lanzetta, Luca Capone, Martina Giraffa, Ivana Russo, Francesco Cicone, Alessandro Bozzao, Filippo Alongi, Luca Nicosia, Gioia Fineschi, Luca Marchetti, Tommaso Tufo, Federico Bianciardi, Vincenzo Esposito, PierCarlo Gentile, Sergio Paolini
Journal for ImmunoTherapy of Cancer 2021;9:e003730 (23 December 2021)

Research

Summary:

Postoperative stereotactic radiosurgery significantly enhances disease control for brain metastases compared to resection alone, however, the development of leptomeningeal disease is a risk secondary to the combination of radiation and surgery. Immunotherapy has demonstrated efficacy for the treatment of brain metastases and for leptomeningeal disease. In a retrospective study that evaluated 129 patients with non-small cell lung cancer and melanoma brain metastases from Giuseppe Minniti et al, the addition of nivolumab or pembrolizumab to stereotactic radiosurgery significantly reduced the incidence of leptomeningeal disease. The 12-month cumulative rates of leptomeningeal disease were 22% (95% CI 14% to 37%) in the stereotactic radiosurgery alone group compared to 6% (95% CI 2% to 17%) in the group that received the immunotherapy combination treatment. Overall survival at 1 year was also higher in the group that received immunotherapy. Treatment-related imaging changes suggestive of radiation-induced brain necrosis were observed in 22 patients in the combination group and 9 in the stereotactic radiosurgery alone group. The study paves the way for future prospective trials evaluating efficacy and safety of different radiation schedules in combination with immunotherapy in patients with resected brain metastases.

SITC Members Receive 50 Percent Submission Discount in 2022

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 2022.

Become a SITC member today!

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