JITC Digest July 2021


Inside this Issue:

Letter from the Editor

Hello JITC Readers,pedro-romero_1__1_.jpg

For our readers in the northern hemisphere, this month’s JITC digest is arriving at the peak of summer. The warm temperatures offer a natural opportunity to consider what causes a tumor to become immunologically “hot” and the complex crosstalk between immune cells, malignant cells and stroma that often allows T cell-inflamed tumors to escape immune control.
Novel mechanisms that could be exploited to enhance tumor immune-responsiveness are revealed by Julie Niogret and colleagues, who find that follicular helper T cells reinvigorate CD8+ T cell-dependent immunity. Another target is identified by Shuangqing Liu et al, who demonstrate that enhancing autophagy in malignant cells increases susceptibility to chemoimmunotherapy.
Two papers reveal new insight on tumor- and stroma-intrinsic contributions to immunosuppression in the microenvironment. Byung-Seok Kim and colleagues show that type 17 immunity promotes CD8+ T cell exhaustion in tumors, whereas Qi Wu et al identify fatty acid oxidations in macrophages as contributing to M2 polarization.
Finally, Wei Mu and colleagues take advantage of the association between immune infiltration and metabolism along with artificial intelligence to develop and validate a non-invasive imaging-based measure of PD-L1 status.
I wish to conclude this month’s JITC digest with a sincere and heartfelt congratulations and thank you to our editors, reviewers, authors, and readers. Because of your continued dedication and support, JITC has increased its Impact Factor to 13.751 and SCImago Journal Rank to 5.060 this year! I welcome anyone who is interested in getting involved and helping support the journal as we continue to grow to consider becoming a reviewer. Find more information on volunteering to join the JITC family of reviewers in this month’s special feature below.
Warm regards,

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

JITC Editor Picks

Follicular helper-T cells restore CD8+-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy

Julie Niogret, Hélène Berger, Cédric Rebe, Romain Mary, Elise Ballot, Caroline Truntzer, Marion Thibaudin, Valentin Derangère, Christophe Hibos, Léa Hampe, David Rageot, Théo Accogli, Philippe Joubert, Bertrand Routy, James Harker, Frederique Vegran, Francois Ghiringhelli, Fanny Chalmin

Journal for ImmunoTherapy of Cancer 2021;9:e002157 (8 June 2021)


Despite documented associations between intratumoral tertiary lymphoid structures and improved prognosis in several human cancers, the mechanisms by which follicular helper-T cells (Tfh) accumulate within and contribute to controlling tumors remain unknown. Julie Niogret et al identify a new feedback loop contributing to anti-tumor immunity wherein interactions between CD8+ exhausted T cells and Tfh promote reinvigoration of effector functions and immune cell infiltration. In murine models of metastatic lung cancer, adoptive transfer of Tfh-like cells led to B cell-independent tumor control, although interferon gamma and CD8+ T cells were both required. In multiple spontaneous and transplanted murine tumor models, accumulation of cells with a classical Tfh phenotype in the tumor bed was also observed. Blockade of CXCL13 reduced the intratumoral accumulation of Tfh, while CD8+ T cells from the tumor bed were shown to be the population with the highest production of the cytokine. Blockade of TGF-beta attenuated CXCL13 transcript production in CD8+ T cells from the draining lymph node with concomitant decrease in intratumoral Tfh accumulation. Inhibition of IL-21 blunted the anti-tumor effects of adoptively transferred Tfh and reduced the ratio of terminal/precursor exhausted T cells. In vitro, IL-21 enhanced tumor necrosis factor alpha and granzyme B expression without affecting interferon gamma production or proliferation. The efficacy of PD-1 blockade was strongly reduced in Tfh-deficient mice, and analysis of published transcriptomic datasets from patients with non-small cell lung cancer treated with nivolumab or pembrolizumab showed an association between Tfh signatures and exhausted T cell signatures and better prognosis. The data put forth Tfh as a potential biomarker for predicting response to anti-PD-(L)1 as well as a source of targets to reinvigorate CD8+-dependent immunity.

S100A4 enhances protumor macrophage polarization by control of PPAR-gamma-dependent induction of fatty acid oxidation

Shuangqing Liu, Huilei Zhang, Yanan Li, Yana Zhang, Yangyang Bian, Yanqiong Zeng, Xiaohan Yao, Jiajia Wan, Xu Chen, Jianru Li, Zhaoqing Wang, Zhihai Qin

Journal for ImmunoTherapy of Cancer 2021;9:e002548  (18 June 2021)



Tumor associated macrophages (TAMs) undergo a peroxisome proliferator-activated receptor (PPAR)-gamma-dependent metabolic reprogramming upon polarization to a protumoral (M2) phenotype. Macrophage-derived S100A4 (also known as FSP1, MTS1 or metastasin) is identified as a key upstream regulator of this metabolic reprogramming by Shuangqing Liu et al. In murine breast cancer models, systemic and macrophage-specific S100A4 deficiency led to impaired tumor growth as well as reduced numbers of F4/80/CD206 double-positive M2-like TAMs. In vitro, Raw264.7 macrophages lacking S100A4 had dramatically reduced arginase activity after treatment with the M2-polarization cytokine IL-4. No differences in chemosensitivity were seen in vitro between S100A4-deficient macrophages and the parent lines. In vivo, however, tumor regrowth after doxorubicin was delayed when S100A4-deficient macrophages were cotransplanted with 4T1 breast cancer cells into immunocompetent mice. Quantitative proteomics and transcriptomics revealed oxidative phosphorylation as among the most significantly altered pathways in macrophages lacking S100A4. In vitro, the respiratory capacity of IL-4-treated S100A4-deficient macrophages was impaired only when exogenous fatty acid oxidation substrate was present and the cells lacking S100A4 also showed defects in fatty acid uptake and lipid droplet formation under M2-polarizing conditions. In macrophage cell lines, bone marrow-derived macrophages, and TAMs, S100A4 was necessary and sufficient for IL-4-stimulated induction of PPAR-gamma. Analysis of published datasets from human patients treated with chemotherapy showed greater expression of S100A4 predicted reduced relapse-free survival in breast cancer and lower overall survival in ovarian and lung cancer. The mechanistic insights into macrophage plasticity provided by this study identify S100A4 as a potential target to alleviate stromal immunosuppression.

Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer

Byung-Seok Kim, Da-Sol Kuen, Choong-Hyun Koh, Hyung-Don Kim, Seon Hee Chang, Sehui Kim, Yoon Kyung Jeon, Young-Jun Park, Garam Choi, Jiyeon Kim, Keon Wook Kang, Hye Young Kim, Suk-Jo Kang, Shin Hwang, Eui-Cheol Shin, Chang-Yuil Kang, Chen Dong, Yeonseok Chung
Journal for ImmunoTherapy of Cancer
2021;9:e002603 (2 June 2021)


Conflicting results have been reported on whether type 17 immunity supports tumor clearance or promotes tumor growth. Byung-Seok Kim and colleagues establish a role for type 17 immunity in promoting CD8+ T cell exhaustion in tumors. In multiple murine models, depletion of CD4+ T cells led to concomitant accumulation of T cells with exhaustion markers and a proliferative subset of tissue resident-memory-like IL-17-producing CD8+ T cells (Tc17) with impaired cytotoxic capacity. Fate mapping experiments showed that the Tc17 population were stable, and adoptive transfer of Tc17 led to increased numbers of tumor foci in the B16F10 lung metastasis model. Selective depletion of IL-17-producing cells as well as engineered IL-17 deficiency led to lower tumor burden and reduced numbers of terminally exhausted T cells. Pharmacologic inhibition of ROR-gamma-t, the transcription factor required for production of many IL-17 effectors, phenocopied depletion of IL-17-producing cells and deletion of the IL-17 locus. Intriguingly, the accumulation of exhausted T cells seen with CD4+ T cell depletion required, in part, CD11b+Gr-1hi myeloid cells. Data from human patients from The Cancer Genome Atlas confirmed an association between type 17 signature and exhaustion signatures in three tumor types—colorectal adenocarcinoma, liver hepatocellular carcinoma, and malignant melanoma—but low correlation was observed for lung adenocarcinoma. The study sets the groundwork for investigating strategies to modulate type 17 immunity to prevent T cell exhaustion.

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

Qi Wu, Ai-Ling Tian, Bei Li, Marion Leduc, Sabrina Forveille, Peter Hamley, Warren Galloway, Wei Xie, Peng Liu, Liwei Zhao, Shuai Zhang, Pan Hui, Frank Madeo, Yi Tu, Oliver Kepp, Guido Kroemer

Journal for ImmunoTherapy of Cancer 2021;9:e002722 (14 June 2021)



Enhancement of autophagy extends lifespan in model organisms and the pathway also has been shown to facilitate anti-cancer immunosurveillance. From a screen of more than 65,000 compounds, Qi Wu and colleagues identified a cyclolignan alkaloid derived from the mayapple plant called picropodophyllin (PPP) that enhanced the efficacy of immunogenic chemotherapy combined with anti-PD-1 through on-target enhancement of autophagy in malignant cells. In vitro characterization showed that PPP stimulates flux through the autophagosome via a canonical ATG5 and TFEB/TFE-3-dependent pathway. Induction of autophagy by PPP was reduced in cells lacking the insulin-like growth factor 1 receptor (IGF1R). Enforced expression of a constitutively active AKT mutant also eliminated the autophagy-enhancing effects of PPP. In mice orthotopically implanted with weakly immunogenic MCA205 fibrosarcomas, PPP alone and in combination with anti-PD-1 did not reduce tumor growth. PPP enhanced the anti-tumor efficacy of oxaliplatin, and the triple combination of chemotherapy with PD-1 blockage and autophagy enhancement showed strong anti-tumor effects in fibrosarcoma and lung cancer modes. Expression of the ecto-ATPase CD39 eliminated the antitumor effects of PPP, supporting a role for extracellular ATP in the response. Mature T lymphocytes were required for therapeutic efficacy, and immunocompetent mice that were cured by the combination resisted rechallenge. The robust anti-tumor responses with triple therapy were also seen with IGF1R inhibition—a combination of oxaliplatin plus PD-1 blockade and the potent and specific inhibitor lintisinib led to several complete remissions and the establishment of immunological memory. In samples from 49 stage negative breast cancer patients treated by surgical resection, activating phosphorylation of IGF1R by immunohistochemistry was associated with poor overall survival along with fewer infiltrating CD8+ T cells. PPP has already demonstrated tolerability in early phase human trials, and IGF1R may be a novel druggable target to enhance the efficacy of chemoimmunotherapy combinations.

Non-invasive measurement of PD-L1 status and prediction of immunotherapy response using deep learning of PET/CT images

Wei Mu, Lei Jiang, Yu Shi, Ilke Tunali, Jhanelle E Gray, Evangelia Katsoulakis, Jie Tian, Robert J Gillies, Matthew B Schabath

Journal for ImmunoTherapy of Cancer 2021;9:e002118 (16 June 2021)



Based on demonstrated associations between immune infiltration, expression of checkpoint proteins, and metabolic rate, Wei Mu and colleagues develop a non-invasive 18F-FDG-PET-based measure of PD-L1 expression. Images and clinical data from 697 patients with non-small cell lung cancer from three institutions were analyzed by a small-residual-convolutional-network to develop a deeply learned score (DLS) for PD-L1 expression. The DLS was validated in accordance with the FDA guidance document for the Clinical Evaluation of Software as a Medical Device (SaMD) using multiple external test cohorts, in which it accurately differentiated between PD-L1-positive and -negative tumors as measured by immunohistochemistry. High DLS was associated with worse progression-free and overall survival in all cohorts, and the predictive power for the imaging based score was not different than for PD-L1 immunohistochemistry. Multivariate models incorporating the DLS, ECOG status, and disease histology predicted outcomes in good agreement with actual observations across cohorts. Notably, visualization of the deep learning model revealed the necrotic region as the self-learned important area for classifying PD-L1 status, indicating the importance of peritumoral immune infiltration and stromal inflammation for immunotherapy responses. Pending validation in prospective trials, imaging-based measurement of PD-L1 expression may offer a non-invasive method for identifying eligibility for checkpoint blockade.


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Popular Archive Articles

The selections below represent some of the most popular content published in JITC over the past few years. Explore additional thematic content in JITC's Collections or access the rest of JITC's archives for a look at all the journal has to offer.

Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience

Omar Mamlouk, Umut Selamet, Shana Machado, Maen Abdelrahim, William F. Glass, Amanda Tchakarov, Lillian Gaber, Amit Lahoti, Biruh Workeneh, Sheldon Chen, Jamie Lin, Noha Abdel-Wahab, Jean Tayar, Huifang Lu, Maria Suarez-Almazor, Nizar Tannir, Cassian Yee, Adi Diab, Ala Abudayyeh

Journal for ImmunoTherapy of Cancer 2019;7:2 (6 January 2019)
Short Report

Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

Elena Verzoni, Giacomo Cartenì, Enrico Cortesi, Diana Giannarelli, Andrea De Giglio, Roberto Sabbatini, Sebastiano Buti, Sabrina Rossetti, Francesco Cognetti, Francesca Rastelli, Alberto Sobrero, Daniele Turci, Cora N. Sternberg, Camillo Porta, Federico Cappuzzo, Giampaolo Tortora, Davide Tassinari, Stefano Panni, Antonio Pazzola, Gianmarco Surico, Alessandra Raimondi, Ugo De Giorgi, Giuseppe Procopio, on behalf of the Italian Nivolumab Renal Cell Cancer Early Access Program group

Journal for ImmunoTherapy of Cancer 2019;7:99  (3 April 2019)


Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature

Noha Abdel-Wahab, Houssein Safa, Ala Abudayyeh, Daniel H. Johnson, Van Anh Trinh, Chrystia M. Zobniw, Heather Lin, Michael K. Wong, Maen Abdelrahim, A. Osama Gaber, Maria E. Suarez-Almazor, Adi Diab
Journal for ImmunoTherapy of Cancer
2019;7:106 (16 April 2019)

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC)

Ezra E. W. Cohen, R. Bryan Bell, Carlo B. Bifulco, Barbara Burtness, Maura L. Gillison, Kevin J. Harrington, Quynh-Thu Le, Nancy Y. Lee, Rom Leidner, Rebecca L. Lewis, Lisa Licitra, Hisham Mehanna, Loren K. Mell, Adam Raben, Andrew G. Sikora, Ravindra Uppaluri, Fernanda Whitworth, Dan P. Zandberg, Robert L. Ferris

Journal for ImmunoTherapy of Cancer 2020;7:184 (15 July 2019)

Position Article and Guidelines

Correlation of plasma exosomal microRNAs with the efficacy of immunotherapy in EGFR/ALK wild-type advanced non-small cell lung cancer

Xiao-Xiao Peng, Ruoying Yu, Xue Wu, Shu-Yu Wu, Can Pi, Zhi-Hong Chen, Xu-Chao Zhang, Cun-Yi Gao, Yang W Shao, Li Liu, Yi-Long Wu, Qing Zhou

Journal for ImmunoTherapy of Cancer 2020;8:e000376 (19 January 2020)


SITC Members Receive 50 Percent Submission Discount in 2021

*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 2021.